Nanoparticles in Modern Antimicrobial and Antiviral Applications (Nanotechnology in the Life Sciences) 303150092X, 9783031500923

Citation preview

Nanotechnology in the Life Sciences

Varaprasad Kokkarachedu Rotimi Sadiku   Editors

Nanoparticles in Modern Antimicrobial and Antiviral Applications

Nanotechnology in the Life Sciences Series Editor Ram Prasad, Department of Botany Mahatma Gandhi Central University Motihari, Bihar, India

Nano and biotechnology are two of the 21st century’s most promising technologies. Nanotechnology is demarcated as the design, development, and application of materials and devices whose least functional make up is on a nanometer scale (1 to 100 nm). Meanwhile, biotechnology deals with metabolic and other physiological developments of biological subjects including microorganisms. These microbial processes have opened up new opportunities to explore novel applications, for example, the biosynthesis of metal nanomaterials, with the implication that these two technologies (i.e., thus nanobiotechnology) can play a vital role in developing and executing many valuable tools in the study of life. Nanotechnology is very diverse, ranging from extensions of conventional device physics to completely new approaches based upon molecular self-assembly, from developing new materials with dimensions on the nanoscale, to investigating whether we can directly control matters on/in the atomic scale level. This idea entails its application to diverse fields of science such as plant biology, organic chemistry, agriculture, the food industry, and more. Nanobiotechnology offers a wide range of uses in medicine, agriculture, and the environment. Many diseases that do not have cures today may be cured by nanotechnology in the future. Use of nanotechnology in medical therapeutics needs adequate evaluation of its risk and safety factors. Scientists who are against the use of nanotechnology also agree that advancement in nanotechnology should continue because this field promises great benefits, but testing should be carried out to ensure its safety in people. It is possible that nanomedicine in the future will play a crucial role in the treatment of human and plant diseases, and also in the enhancement of normal human physiology and plant systems, respectively. If everything proceeds as expected, nanobiotechnology will, one day, become an inevitable part of our everyday life and will help save many lives.

Varaprasad Kokkarachedu  •  Rotimi Sadiku Editors

Nanoparticles in Modern Antimicrobial and Antiviral Applications

Editors Varaprasad Kokkarachedu Facultad de Ingeniería Arquitectura y Diseño University of San Sebastián Concepción, Chile

Rotimi Sadiku Department of Chemical, Metallurgical and Materials Engineering Institute for Nano Engineering Research (INER) Tshwane University of Technology Pretoria, South Africa

ISSN 2523-8027     ISSN 2523-8035 (electronic) Nanotechnology in the Life Sciences ISBN 978-3-031-50092-3    ISBN 978-3-031-50093-0 (eBook) https://doi.org/10.1007/978-3-031-50093-0 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Contents

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced Healthcare Applications��������������������������������������������    1 Varaprasad Kokkarachedu, Daniel Cole Cid, Tippabattini Jayaramudu, Rotimi Sadiku, Rodrigo Cáceres Congreve, Carolina Paz Quezada, Natarajan Sisubalan, and Karthikeyan Chandrasekaran Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications and Theranostic Potential ������������������������������������   19 Muniraj Gnanaraj, Natarajan Sisubalan, T. Jebastin, Arumugam Vijayan, T. Muneeshwaran, and R. Manikandan Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral Perspectives������������������������������������������������������������������������������   47 S. Shiva Samhitha, Srivathsava Surabhi, Sai Keerthi Saireddy, and G. Santhosh SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential Applications��������������������������������������������������������������������������������������   65 Varaprasad Kokkarachedu, Karthikeyan Chandrasekaran, Natarajan Sisubalan, Tippabattini Jayaramudu, Arumugam Vijayan, and Rotimi Sadiku CuO Nanoparticles for Antimicrobial/Antiviral Applications ��������������������   97 Tippabattini Jayaramudu and Varaprasad Kokkarachedu Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis, Antimicrobial Properties, and Toxicity Considerations ��������  119 B. A. Aderibigbe Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral Applications������������������������������������������������������������������������������  151 Pranav Pandya and Sougata Ghosh

v

vi

Contents

 Cerium Oxide Nanoparticles for Biomedical Applications��������������������������  175 Arumugam Vijayan, Shalini Ramadoss, Natarajan Sisubalan, Muniraj Gnanaraj, Karthikeyan Chandrasekaran, and Varaprasad Kokkarachedu Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances, Challenges, and Future Prospects ����������������������  201 Natarajan Sisubalan, Shalini Ramadoss, Muniraj Gnanaraj, Arumugam Vijayan, Karthikeyan Chandrasekaran, Sivamaruthi Bhagavathi Sundaram, Chaiyasut Chaiyavat, and Varaprasad Kokkarachedu Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral, and Anticancer Therapies������������������������������������  227 Karthikeyan Chandrasekaran, Varaprasad Kokkarachedu, Natarajan Sisubalan, Arumugam Vijayan, P. Hendry Moses, P. Edison Raj Godwin, C. Kelvin Adaikalam, S. Gowri, J. Jason Mathews, A. S. Haja Hameed, and J. Ebenezar  NiO Nanoparticles for Advanced Clinical Applications ������������������������������  243 Adil M. Allahverdiyev, Buşra Akgül, Jahid Alakbarli, Sedanur Keleş, Malahat Baghırova, and Emrah Ş. Abamor Aluminum Oxide Nanoparticles: Properties and Applications Overview ����������������������������������������������������������������������������������������������������������  265 Rodrigo Cáceres Congreve, Carolina Paz Quezada, and Varaprasad Kokkarachedu Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications������������������������������������������������������������������������������  289 Rishikesh Kumar, Namrata Kumari, and Ganesh C. Sahoo MXene-Based Nanocomposites for Antibacterial Applications ������������������  305 Aditya Velidandi, N. Jayarambabu, P. Geetha, and Varaprasad Kokkarachedu  arbon Nanotubes for Antimicrobial and Antiviral Applications: C Immunological Aspects, Developments, and Challenges������������������������������  331 Adil M. Allahverdiyev, Sedanur Keleş, Buşra Akgül, Jahid Alakbarli, Malahat Baghırova, and Emrah Ş. Abamor  Carbon Quantum Dots for Medical Applications ����������������������������������������  367 Chelladurai Karthikeyan Balavigneswaran and Vignesh Muthuvijayan Graphene Oxide: A Promising Nanomaterial for Antibacterial and Antiviral Applications������������������������������������������������������������������������������  389 Carolina Paz Quezada, Rodrigo Cáceres Congreve, and Varaprasad Kokkarachedu Index������������������������������������������������������������������������������������������������������������������  421

Contributors

Emrah  Ş.  Abamor  Department of Bioengineering, Yıldız Technical University, Istanbul, Turkey C.  Kelvin  Adaikalam  Cauvery College for women, Autonomous (Affiliated to Bharathidasan University), Tiruchirappalli, Tamil Nadu, India B.  A.  Aderibigbe  Department of Chemistry, Alice Campus, University of Fort Hare, Alice, South Africa Buşra  Akgül  Department of Bioengineering, Yıldız Technical University, Istanbul, Turkey Jahid  Alakbarli  The V.  Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan Department of Bioengineering, Yıldız Technical University, Istanbul, Turkey Adil  M.  Allahverdiyev  The V.  Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan Malahat Baghırova  The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan Chelladurai  Karthikeyan  Balavigneswaran  Department of Biotechnology, Tissue Engineering and Biomaterials Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India Chaiyavat Chaiyavat  Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand Karthikeyan  Chandrasekaran  Department of Chemical and Biochemical Engineering, Dongguk University, Seoul, Republic of Korea KIRND Institute of Research and Development PVT LTD, Tiruchirappalli, Tamil Nadu, India

vii

viii

Contributors

Daniel Cole Cid  Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile Rodrigo  Cáceres  Congreve  Departamento de Química Ambiental, Facultad de Ciencias, Universidad Católica de la Santísima, Concepción, Chile J. Ebenezar  Jamal Mohamed College, Autonomous (Affiliated to Bharathidasan University), Tiruchirappalli, Tamil Nadu, India P. Geetha  Sri Venkateswara College of Engineering Karakam badi, Tirupathi, India Sougata Ghosh  Department of Microbiology, School of Science, RK. University, Rajkot, Gujarat, India Muniraj  Gnanaraj  Department of Biotechnology & Bioinformatics, Bishop Heber College (Autonomous), Trichy, Tamil Nadu, India P. Edison Raj Godwin  Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand S. Gowri  Cauvery College for women, Autonomous (Affiliated to Bharathidasan University), Tiruchirappalli, Tamil Nadu, India A.  S.  Haja  Hameed  Jamal Mohamed College, Autonomous (Affiliated to Bharathidasan University), Tiruchirappalli, Tamil Nadu, India N. Jayarambabu  Department of Biotechnology, National Institute of Technology, Warangal, Telangana, India Tippabattini Jayaramudu  Department of Biomedical Engineering, University of Memphis, Memphis, TN, USA T. Jebastin  Department of Biotechnology & Bioinformatics, Bishop Heber College (Autonomous), Trichy, Tamil Nadu, India Sedanur  Keleş  Department of Nanoscience and Nanoengineering, Ataturk University, Erzurum, Turkey Varaprasad  Kokkarachedu  Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile Rishikesh  Kumar  Department of Microbiology, Molecular/Drug Delivery Lab, Indira Gandhi Institute of Medical Science Patna, Patna, Bihar, India Namrata  Kumari  Department of Microbiology, Molecular/Drug Delivery Lab, Indira Gandhi Institute of Medical Science Patna, Patna, Bihar, India R.  Manikandan  Padmavani Arts & Science College for Women, Opp. Periyar University, Salem, Tamil Nadu, India J.  Jason  Mathews  Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand

Contributors

ix

P.  Hendry  Moses  Jamal Mohamed College, Autonomous (Affiliated to Bharathidasan University), Tiruchirappalli, Tamil Nadu, India T.  Muneeshwaran  Department of Health Sciences, Lab of Toxicology, The Graduate School of Dong-A University, Busan, Republic of Korea Vignesh  Muthuvijayan  Department of Biotechnology, Tissue Engineering and Biomaterials Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India Pranav Pandya  Department of Microbiology, School of Science, RK. University, Rajkot, Gujarat, India Carolina  Paz  Quezada  Departamento de Química Ambiental, Facultad de Ciencias, Universidad Católica de la Santísima, Concepción, Chile Rotimi Sadiku  Department of Chemical, Metallurgical & Materials Engineering, Institute of Nano Engineering Research (INER), Tshwane University of Technology, Pretoria West Campus, Pretoria, Republic of South Africa Ganesh  C.  Sahoo  Department of Microbiology, Nanomedicine/Virology Lab, Rajendra Memorial Research Institute of Medical Science Patna, Patna, Bihar, India Sai  Keerthi  Saireddy  Department of General Medicine, Chalmeda Anand Rao Institute of Medical Sciences, Karimnagar, Telangana, India S.  Shiva  Samhitha  Department of Materials Engineering (DIMAT), Research Group in Advanced Nanocomposites (GINA), Faculty of Engineering, University of Concepción, Concepción, Chile G. Santhosh  Department of Mechanical Engineering, Nano-Materials and Energy Devices Lab (NMEDL), NMAM Institute of Technology, Nitte (Deemed to be University), Deralakatte, Karnataka, India Shalini Ramadoss  Department of Botany, Bishop Heber College (Autonomous), Affiliated to Bharathidasan University, Tiruchirappalli, TN, India Natarajan Sisubalan  Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand Department of Botany, Bishop Heber College (Autonomous), Affiliated to Bharathidasan University, Tiruchirappalli, TN, India Sivamaruthi  Bhagavathi  Sundaram  Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand Office of Research Administration, Chiang Mai University, Chiang Mai, Thailand Srivathsava  Surabhi  Department of Materials Engineering (DIMAT), Research Group in Advanced Nanocomposites (GINA), Faculty of Engineering, University of Concepción, Concepción, Chile

x

Contributors

Nanosciences and Nanotechnology Laboratory, Faculty of Mathematical Physical Sciences (FCFM), Universidad Autónoma de Nuevo León (UANL), San Nicolás de los Garza, Nuevo León, Mexico Aditya  Velidandi  Department of Physics, National Institute of Technology, Warangal, Telangana, India Arumugam Vijayan  Department of Microbiology, Faculty of Health and Medical Sciences, SRM Institute of Science and Technology, Tiruchirappalli, Tamil Nadu, India

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced Healthcare Applications Varaprasad Kokkarachedu, Daniel Cole Cid, Tippabattini Jayaramudu, Rotimi Sadiku, Rodrigo Cáceres Congreve, Carolina Paz Quezada, Natarajan Sisubalan, and Karthikeyan Chandrasekaran

Overview In a world where advances in science and medicine have a refined growth, so are bacteria, microbes and viruses, with ripened resistance against drugs over time, causing these pathogens to no longer respond to conventional treatments and hence, leaving a large part of the population vulnerable to infections and diseases (Varaprasad et al., 2020a). That is the reason why the development and the study of new tools to combat pathogens, have been among the most important, in recent

V. Kokkarachedu (*) · D. C. Cid Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile e-mail: [email protected] T. Jayaramudu Department of Biomedical Engineering, University of Memphis, Memphis, TN, USA R. Sadiku Department of Chemical, Metallurgical & Materials Engineering, Institute of Nano Engineering Research (INER), Tshwane University of Technology, Pretoria West Campus, Pretoria, Republic of South Africa R. C. Congreve · C. P. Quezada Departamento de Química Ambiental, Facultad de Ciencias, Universidad Católica de la Santísima, Concepción, Chile N. Sisubalan Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand K. Chandrasekaran Department of Chemical and Biochemical Engineering, Dongguk University, Seoul, Republic of Korea © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_1

1

2

V. Kokkarachedu et al.

times. An exciting proposal to combat these problems is the bio-designed nanoparticles due to their application capabilities as antibiotics. This is due to their physical and chemical compositions; hence, these antibiotic materials have been implemented in biomedical applications for the treatment of infectious diseases (Varaprasad et al., 2020b, 2022). Silver (Ag) is an inorganic material, which has been used for over 5000 years to prepare (jewelry) materials (Barillo & Marx, 2014). According to the reports, Ag was actively used in World War I to cure soldiers’ wounds in order to control infections and for rapid wound healing (Medici et al., 2019). Therefore, the properties of Ag have been known for many years and it has been used for disinfection and to conserve drinking water quality and for many other applications. However, the first apparition of Ag in the form of nanoparticles appeared in 1889, when Ag was synthesized with citrate for therapeutic applications in medicine. In addition, it was described as early as 1902 for the stabilization of nanoAg by using proteins. Various preparations have long been used for the production of Ag nanoparticles, specifically because of their bactericidal properties in the treatment of chronic diseases. In the seventeenth and eighteenth centuries, silver nitrate salts were used for the treatment of ulcers, and later on in the 1960s, it was introduced in treating burns. The introduction of antibiotics in 1940 led to a decrease in their use due to their toxic effect on living cells. Ag nanomaterials play a fundamental role in modern health applications as a new medical tool since they can improve physicochemical and biological characteristics (Rozhin et al., 2021). Lately, to improve Ag applicability in the medical field, it was synthesized by the green process. In addition, its interfaces were modified with other organic and inorganic materials. However, nanomaterials can enhance the solubility of compounds, reduce antiviral and antibacterial side effects, improve drug and vaccine delivery, improve the shape fidelity and resolution of 3D scaffolds often used for tissue regeneration and improve the immune response, acting as adjuvants. In this chapter, we will discuss nano Ag and its derivative materials and how they can be of help in the control of pathogens and viruses (COVID-19).

Advantages and Disadvantages of Ag The main Ag disadvantages are cost and may become toxic at high concentrations. The Ag salt (silver nitrate, silver sulphonamides, silver sulphadiazine) forms have shown disadvantages in the living system, such as when they are applied on humans, they have a high solubility in human serum (physiological conditions), and human skin can have more absorption of Ag+ (Liang et al., 2018). However, the bulk size form of Ag can delay the infection control process (Varaprasad et al., 2010). In order to avoid this, Ag is employed in the form of colloidal suspension or nano Ag, which can enter into pathogenic bacteria and viruses and release the active free radicals in a controlled manner, thereby, improving the overall therapeutic modalities (Varaprasad et al., 2011).

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced…

3

Nano Ag has been shown to easily bind with thiol, amino and carboxyl functional groups of amino acid residues of proteins and nucleic acids (Nandhini et al., 2023; Rodrigues et al., 2021). This binding can lead to the prevention of pathogenic bacteria by disrupting their cellular functions. The binding of nano Ag with thiol groups can cause the release of Ag ions, which can interact with bacterial cell membranes and disrupt their integrity. Additionally, the binding of nano Ag with carboxyl groups can interfere with bacterial enzyme activity and disrupt their metabolic pathways. The binding of nano Ag with amino groups can also cause damage to bacterial DNA, leading to cell death. Overall, the ability of nano Ag to bind with multiple functional groups of proteins and nucleic acids makes it a promising candidate for developing antimicrobial agents. Nano Ag’s electrical conductivity, sufficient chemical stability, catalytic, antimicrobial and antiviral properties make it a versatile material with a wide range of applications. Its ability to conduct electricity makes it useful in electronic devices, while its chemical stability allows it to be used in harsh environments. Its catalytic properties make it useful in chemical reactions, and its antimicrobial and antiviral properties make it a promising candidate for developing healthcare applications. One of the key advantages of nano Ag is that it does not cause an unpleasant odour and does not create toxic substances, making it safe for use in various applications. In water treatment, nano Ag is used to inhibit the growth of bacteria, fungi, spores and algae. This makes it a reliable and safe option for improving water quality. Furthermore, studies have shown that nano Ag is safe for human and animal health at minimum concentrations. It does not have any harmful effects on humans or animals, making it a promising material for various biomedical applications such as wound dressings, drug delivery systems and implant coatings. Overall, the unique combination of properties and safety profile of nano Ag make it a promising material for a wide range of applications in various fields including electronics, catalysis, healthcare and water treatment. However, nano Ag has several advantages and disadvantages that are important to consider when evaluating its potential use in various applications. Advantages: (a) Antimicrobial properties: Nano Ag exhibits potent antimicrobial properties against a wide range of bacteria, viruses and fungi (Morones et al., 2005; Sondi & Salopek-Sondi, 2004). This makes it a promising candidate for developing antimicrobial and antiviral agents for healthcare applications. (b) Biocompatibility: Compared to other inorganic nanomaterials, nano Ag has been found to be more biocompatible and less toxic to living cells (Sharma et al., 2009; Sondi & Salopek-Sondi, 2004). This makes it a safer option for biomedical applications. (c) Environmental sustainability: The synthesis process of biogenic nano Ag using biological sources such as plants, fungi and bacteria is environmentally friendly and sustainable (Raj et al., 2021). It does not require the use of toxic chemicals, and the biological sources used are readily available and renewable. (d) Versatility: Nano Ag can be used to prepare various next-­ generation materials such as vaccines, antibiotics and wound dressings for healthcare applications due to its bio/physicochemical properties (Arjun et al., 2022; Pilaquinga et al., 2021).

4

V. Kokkarachedu et al.

Disadvantages: (a) Potential toxicity: The toxicity of nano Ag on living cells is still not fully understood, and high concentrations of nano Ag can lead to increased toxicity (AshaRani et  al., 2012; Sayes et  al., 2004). Therefore, it is important to ensure that nano Ag is developed in a safe and effective manner to minimize any potential harm to living cells. (b) Cost: The cost of synthesizing nano Ag can be higher compared to other inorganic nanomaterials, which may limit its widespread use in various applications (Tripathi et  al., 2019). (c) Stability: Nano Ag can be unstable in certain environments, such as in the presence of organic matter or under certain pH conditions (Sharma et al., 2009). This can affect its efficacy as an antimicrobial agent. (d) Regulatory challenges: The use of nano Ag in various applications may face regulatory challenges due to concerns about its potential toxicity and environmental impact (Auffan et al., 2009). In summary, nano Ag has several advantages and disadvantages that should be considered when evaluating its potential use in various applications. While it has shown great promise as an antimicrobial and antiviral agent for healthcare applications, further research is needed to fully understand its toxicity, stability and regulatory challenges.

Advantages of Biogenic Nano Ag Biogenic nano Ag refers to Ag nanoparticles that are synthesized by using biological sources such as plants, fungi and bacteria (Raj et al., 2021). Biogenic nano Ag has numerous advantages over chemically synthesized Ag nanoparticles, including environmental sustainability, biocompatibility and lower toxicity. Biogenic nano Ag exhibits strong antimicrobial and antiviral properties, making it useful for various applications. Studies have shown that biogenic nano Ag can effectively inhibit the growth of various bacteria, including antibiotic-resistant strains such as Methicillin-­ resistant Staphylococcus aureus (MRSA), and has antiviral activity against several viruses, including Human immunodeficiency virus (HIV), herpes simplex and influenza. Recent studies have investigated the antimicrobial and antiviral properties of biogenic nano Ag synthesized by using the plant extract of Cassia auriculata and the fungus Aspergillus terreus (Kamaraj et  al., 2023; Srinivasan et  al., 2015). These studies found out that biogenic nano Ag exhibited strong antibacterial and antiviral activities against pathogenic bacteria and viruses, respectively. Overall, biogenic nano Ag offers numerous advantages and has potential as a candidate for developing antimicrobial and antiviral therapies. However, further research is needed to fully understand its mechanisms and evaluate its safety and efficacy in humans.

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced…

5

Toxicity Effect (a Mechanism) on Living Cells The toxicity of nano Ag on living cells is an important consideration in the development of safe and effective nanomaterials for healthcare applications. Studies have shown that the toxicity of nano Ag on living cells is dependent on various factors, such as: size, shape, surface area and concentration of the nanoparticles. In general, smaller nanoparticles tend to be more toxic than  their larger  counterparts due to their greater surface area and the ability to penetrate cell membranes more easily. The shape of the nanoparticles can also affect their toxicity, with nanoparticles that have a high aspect ratio (e.g., nanowires) being more toxic than those with a low aspect ratio (such as spherical nanoparticles). The toxicity of nano Ag on living cells can also be influenced by the concentration of the nanoparticles. High concentrations of nano Ag can lead to increased toxicity, while lower concentrations may have little to no effect on living cells. The mechanism by which nano Ag exerts its toxic effects on living cells is not fully understood. However, several studies have suggested that nano Ag can induce oxidative stress in cells, leading to damage to cellular components such as DNA, proteins and lipids. This can ultimately lead to cell death or dysfunction. Overall, the toxicity of nano Ag on living cells is a complex issue that requires further investigation. While nano Ag has shown great potential as an antimicrobial and antiviral agent for healthcare applications, it is important to ensure that it is developed in a safe and effective manner to minimize any potential harm to living cells.

 ecent Investigations on the Toxicity Effect of Nano Ag R (a Mechanism) on Living Cells Ag has oligodynamic effects, which are the biocidal effects of nanomaterials (Salleh et al., 2020). Therefore, they are used in a significant, but low concentration to control antiviral and antibacterial pathogens. Nanoparticles’ oligodynamic or toxicity effect mainly depends on their (physiochemical properties), viz size, surface area, concentration, shape, agglomeration state and compositions (Franzolin et al., 2022). In addition, it depends on the cell type (Ferdous & Nemmar, 2020). Generally, nano Ag shows cytotoxicity by generating oxidative stress via different mechanisms. These nanoparticles enter different cells and disturb the mitochondrial membrane by the production of radical oxygen species (ROS), which can cause DNA damage (Beus et al., 2023). The antibacterial activity of the Ag increases when their size is small, which is less toxic to living cells (organs). However, they generate cytotoxicity in mammalian, keratinocytes and fibroblast cells (Peetsch et al., 2013; Puccetti et al., 2023). In order to control this toxicity, they are developed via a green process by using secondary metabolisms(Karthikeyan et al., 2021; Mendes et al., 2022). In addition, they grow with biopolymers in order to improve their biosafety and

6

V. Kokkarachedu et al.

biocidal properties (Hoyo et al., 2020). The Ag-based nanomaterial’s antimicrobial characteristics were also improved by the addition of conducting polymers, which can enhance their electrical conductivity and provide antibacterial and osteogenic properties (Sudhisha et al., 2023). In addition, silver–platinum (AgPt) nanoparticles exhibit low toxicity on human embryonic kidney cells (HEK293) due to the antioxidant effect of platinum (Sathiyaseelan et al., 2022). Table 1 shows the recent studies on the toxicity effect on living cells and bacterial pathogens of Ag and Ag-based nanomaterials. However, several researchers have employed in  vitro cytotoxicity studies to characterize the Ag nanoparticles’ biological response. In vivo bio-­ distribution and toxicity studies in animal models have shown that nano Ag exhibits toxicity in living organs. Overall, non-toxic Ag nanoparticles should find use in biomedical applications and need more effective investigations for the development of innovative nanomaterials for the next generation of biomedical applications.

Recent Reports/Studies on COVID-19 Applications COVID-19 has a high mutation rate of ribonucleic acid (RNA) containing viruses. According to recent reports, inorganic material surfaces have been used effectively to control bacterial and viral transitions (Meister et al., 2022). However, in order to control this virus, effective personal protective equipment and vaccines are needed. Generally, nano  Ag has been used to inhibit around 650 pathogens and viruses within 5–7 min (Medici et al., 2019; Morozova et al., 2022). In addition, Ag and its derivative biomaterials are effectively used to control several pathogens and viruses (Herpes, Influenza, HIV, Ebola, West Nile and SARS) (Pasparakis, 2022). Especially, for COVID-19 protection, several Ag-functionalized face masks are available in the commercial market (Blevens et  al., 2021) (10.1021/acs.chas.1c00005). Since Ag nanoparticles can release active (superoxide, hydroxyl) radicals when they are exposed to light irradiation, they can interact (electrostatically) with negatively charged pathogens (block DNA replication), inhibit pathogen growth and damage viral envelopes. Ag+ ions control and destroy RNA and DNA, therefore, inhibiting viral genome replication. Figure 1a, b explains the nano Ag’s possible antimicrobial and antiviral mechanisms. Nano Ag or Ag-based nanomaterials can interact with the spike glycoprotein of the virus and consequently damage the binding of the virus for the cells (Salleh et al., 2020). The release of catatonic Ag, which can reduce the pH of the respiratory epithelium to develop into an effective acid (which is unfriendly towards the virus), can cause the inhibition of the virus. According to reports, it has been used against several viruses, such as human immunodeficiency, chikungunya, severe and acute respiratory syndrome corona, herpes simplex virus, and others (Blevens et al., 2021). However, the small size (⁓10  nm) of Ag nanoparticles can effectively inhibit extracellular severe acute respiratory syndrome  of the Coronavirus-2 (SARS-­ CoV-­2) viruses (Jeremiah et al., 2020). According to the reports, above 1 ppm concentration of Ag effectively controls the virus. In addition, Ag nanoparticles showed

AgPt, AgPt nanoparticles fabricate cotton gauze

Zizania latifolia extract/Ag nanoparticles

Ag nanoparticles

Living cells MG63: cell viability 98% and proliferation 123% Human mesenchymal stem cells (toxic at 1.0–2.5 μg Ag mL−1)

Bacterial pathogens Staphylococcus (99.6% inhibition) Escherichia coli (99.8% inhibition) Staphylococcus aureus (for inhibition, need 0.62–3 μg Ag mL−1). Escherichia coli, Staphylococcus aureus (for inhibition, need 0.62–3 μg Ag mL−1) K. pneumoniae (256 μg/mL), S. aureus (256 μg/mL and MBS 512), P. aeruginosa (32 μg/mL), E. coli (64 μg/mL)

Breast cancer (MCF-7) (63 μg/mL) Human melanoma (A375) (55.41 μg/mL) Adenocarcinomas human alveolar basal epithelial (A549) (100 μg/mL) Liver Hepatocellular carcinoma (HeG2) (14.58 μg/ mL) 50 nm NIH 3T3 fibroblast cell line B. subtilis, (50 μg/mL, not shown toxic P. aeruginosa, Escherichia coli, to cells) Staphylococcus aureus, B. cereus (MIC50 1.95 μg/mL), S. aureus 21.48 ± 6.32 nm Human embryonic kidney cells (HEK-293) (145 μg/ (1.95 μg/mL), E. coli (1.95–3.9 μg/mL), S. mL), Pancreatic cancer cells enterica (0.97 μg/mL), C. albicans, A. flavus, (110 μg/mL) A. fumigatus, A. niger.

23 nm

Size of Silver-based nanomaterials Nanoparticles Ag/poly(3,4,ethylenedioxythiphene)/ – Titanium nanotubes Ag-doped calcium phosphate 50–60 nm nanoparticles

Table 1  Recent studies on the toxicity effects of Ag and Ag-based nanomaterials on living cells and bacterial pathogens

(continued)

Satheesh et al., (2022)

Satheesh et al., (2022)

Wypij et al., (2022)

References Sudhisha et al., (2023) Peetsch et al. (2013)

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced… 7

Alternanthera sessilis Ag nanoparticles Ag/AgCℓ/alginate

Silver-based nanomaterials Sargassum pbolycystum Ag nanoparticles

Table 1 (continued)

L929 cell lines Human dermal fibroblast (HuDe), Keratinocyte (NCTC2544)

25–65 nm

Living cells Zera fish embryo

15–40 nm

Size of Nanoparticles 10–85 nm Bacterial pathogens E. coli (16 μg/mL), Micrococcus luteus, Serratia marcescens, Pseudomonas fluorescens, S. aureus,Vibrio cholerae, Staphylococcus epidermidis, Klebsiella pnemoniae, Bacillus cereus, Candia albicans (32 μg/mL) Klebsiella pneumoniae, Klesiella oxytoca, Acinetobacter baumanii S. aureus, P. aeruginosa, S. epidermidis, Candida albicans

Kabeerdass et al., (2022) Puccetti et al. (2023)

References Thiurunavukkarau et al., (2022)

8 V. Kokkarachedu et al.

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced…

9

Fig. 1 (a) Antimicrobial activities (Salleh et  al., 2020) (Open Access: This article is licensed under a Creative Commons Attribution License, MDPI) and (b) antiviral mechanisms of Ag nanoparticles: (1) interaction of Ag nanoparticles with the viral surface, (2) interface with the cells membrane while blocking the viral attachment, (3) inhibition of cellular pathways of the virus, (4) interaction with viral genome, (5) interaction to inhibit viral genome replication and (6) inhibition of cellular factors (such as protein synthesis) necessary for viral replication (Ratan et al., 2021) (Open Access this article is licensed under a Creative Commons Attribution License, MDPI)

10

V. Kokkarachedu et al.

cytotoxicity from 20 ppm (Jeremiah et al., 2020). Morozova et al. developed different Ag materials, such as Ag+, Ag cystine complexes and Ag nanoclusters that are used against SARS-CoV-2 RNA and the recombinant virion proteins (Morozova et al., 2022). They reported that the combined treatment with Ag cystine and Ag nanoparticles are recommendable in order to reduce the risk of virus resistance. Ag is used for the formulation of immune (antigen-antibody) systems, which can show immunomodulatory potential needed to improve vaccine efficacy (Naz et al., 2023). Therefore, it is used to develop COVID-19 vaccine. This vaccine cures the disease and decreases the spread of the virus. In addition, Ag is used to identify and detect COVID-19. Ag-based testing materials (antigen tests) showed more efficiency and ease in identifying a viral infection than conventional testing materials (Obata et al., 2022). This test is based on Ag amplification and on immunochromatography technology. It is worth noting that this antigen test is simple, cost-­ effective and rapid when compared to the reverse-transcription polymerase chain reaction test (Fig. 2). Ag has a high conductivity, desirable catalytic activity, low heat capacity, good chemical stability and antibacterial capacity (Mendes et  al., 2022). Therefore, researchers are interested in the development of a self-sterilization mask. Liu et al., prepared an electrothermal sterilized and reusable mask (Liu et al., 2023; Yang & Wang, 2020). They specified the fact that they employed Ag micromesh films in the mask. Therefore, the mask exhibited a 95.58% antibacterial capacity within 20 min when 3  V voltage was applied to. In addition, the increased surface temperature (67 °C) endows its thermal sterilization towards pathogens. SARS-CoV and a few other harmful viruses and pathogens showed dead bacteria at this temperature (Liu et al., 2023; Yang & Wang, 2020). Zou et al., also developed antiviral masks with thermal comfortability and self-­ sterilization properties (Zou et al., 2022). The antiviral masks were developed from chitosan-Ag nanomaterials and plant fibre. They reported the fact that Ag-based core/shell nanomaterials enhanced (4.5 times) the thermal conductivity when compared to commercial masks. They are more breathable (air permeability was 167.4 mm/s) and can heat the human body in a cold environment. In addition, they recorded good electrical and antibacterial characteristics. Ag-based nanomaterials (graphitic carbon nitride flakes, encrusted with Ag nanoparticles) were also used to generate self-cleaning and self-disinfecting papers (Maślana et al., 2022). These papers showed significant antibacterial and antiviral properties (COVID-19). These materials can purify contaminated water and can be used as antimicrobial wallpapers in the public sector. Ag is also used for the preparation of mesoporous nanomaterials with other inorganic nanoparticles (Ibrahim, 2022). Its antiviral and antimicrobial efficiencies improved by the addition of quercetin. Under a near-infrared laser irradiation at ⁓1060  nm, they generated heat effectively. Therefore, nanomaterials have a significant inhibition capacity on bacteriophage and COVID-19. In addition, they have superior cellular uptake properties. Lately, in order to control the transmission of disease from mobile phones, silver oxide (Ag2O)-coated screen protectors have been developed. According to the report, 2.4  mg of Ag2O per mm2-coated screen protectors can have a 99.3%

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced…

11

Fig. 2  The possible mechanism of action towards severe acute respiratory syndrome Coronavirus 2 (Salleh et al., 2020) (Open Access; this article is licensed under a Creative Commons Attribution License, MDPI)

inhibition of SARS-CoV-2 (Hosseini et al., 2022). In addition, nanoparticles-coated screens can have a 99.5% control of Pseudomonas aeruginosa, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus within 1 h.

12

V. Kokkarachedu et al.

Miscellaneous Antibacterial and Antiviral Applications Ag nanoparticles are used to control fish pathogens, such as bacterial strains (Streptococcus agalactiae, Aeromonas hydrophila, Vibrio alginolyticus) and fungal stains (Aspergillus flavus, Fusarium moniliforme, Candia albicans) (Ghetas et al., 2022). However, these nanoparticles can show slight toxicity effects on fish. In order to control the toxicity of nanoparticles, the green process was used to develop Ag nanoparticles that are safer than the chemically synthesized nanoparticles. In vivo and hemocompatibility studies explained the fact that the greenly synthesized Ag nanoparticles have good biocompatibility and they are safe on zebrafish (Satheesh et al., 2022). Textile fibres have over centuries been used for medical applications (Varaprasad et al., 2020a). Especially, they are employed for infection control and wound healing (Kanikireddy et al., 2020). However, in order to improve their biomedical specifications, they are often modified and functionalized with Ag nanoparticles. The Ag nanoparticles can enhance the gauze properties, such as colouration, UV protection, antiinflammation and antimicrobial activities. Mohamed et al. synthesized the multifunctional hydroxyapatite/Ag nanoparticles/cotton gauze for the control of Candida albicans and other Gram-positive and negative pathogens (Said et  al., 2021). They specified the fact that the Ag nanoparticles are nucleated with ginger oil due to their π-electrons and the associated hydroxyl functional groups. Sathiyaseelan et al. reported that AgPt showed significant antimicrobial and antioxidant activities (2022). These nanomaterials and chitosan were coated on cotton gauze in order to obtain significant antimicrobial and healing properties. Ag nanoparticles are also generated on different natural (cotton, wool, silk) fabrics. Lately, Ag nanoparticles (35.29 ± 6.43 nm size) have been developed by using bacterial (proteins) proteases (they are two types: exopeptidases and endopeptidases) and visible light activation (Siritapetawee et al., 2022). The Ag nanoparticles developed were coated on cotton gauze via immersion and ultrasonication procedures. However, due to the formation of protease-coved Ag/AgCl nanoparticles, it is believed that it can improve the fibrinolytic and collagenolytic activities and also wound healing. In addition, the nanoparticles were strongly functionalized with cotton, which are safe to use for treatment because they cannot be absorbed into living cells. Antibacterial Ag-based bimetallic nanomaterials were prepared in order to obtain advanced physical, chemical and biological properties (Al-Zubeidi et  al., 2021). Lately, copper (Cu) and Ag salts have been used to develop hybrid antibacterial materials via a green process. Ali et al. generated cost-effective Cu–Ag nanoparticles (75.58 nm size) by using beetroot extract (Ali et al., 2023). They specified that the nanomaterials have a potent catalytic (90%), antiradical (on diphenyl picrylhydrazyl, azino-bis-ethylbenzothiazoline-6-sulphonic acid) and antimicrobial activity (on Salmonella typhimurium and Bacillus subtilis). According to the report, silver/ gold-based hybrid nanomaterials can control corrosion and enhance Ag+ delivery. In addition, it enhances biocompatibility, decreases toxicity and is beneficial for use in in vitro and in vivo experiments (Tiedemann et al., 2014).

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced…

13

Conclusion and Future Aspects Antimicrobial and antibacterial inorganic nanomaterials have gained  significant attention as potential agents for controlling bacterial pathogens and viruses. Among them, nano Ag and its derivative nanomaterials have been extensively studied due to their potent antimicrobial properties. Nano Ag has been found to be effective in preventing virus-mediated infections when compared to other inorganic nanomaterials. To understand the toxicity, possible mechanisms of antimicrobial and antiviral action, and recent applications against COVID-19, researchers have investigated the bio/physicochemical properties of nano Ag. These properties have been utilized to prepare various next-generation materials such as vaccines and antibiotics for healthcare applications. However, in order to enhance the applicability of nano Ag in healthcare applications, it is essential to prepare nanotoxic nano Ag and Ag-based nanomaterials for advanced antimicrobial and antiviral applications in the clinical field. This requires cost-effective and eco-friendly methods to prepare a non-toxic nanosilver that can effectively control pathogens and viruses. Therefore, there is a need for sustained investigations to develop safe and effective nanomaterials for healthcare applications. In summary, nano Ag and its derivatives have shown great potential as antimicrobial and antiviral agents for healthcare applications. However, further research is needed to fully understand their mechanisms of action and to develop safe and effective nanomaterials for clinical use. Acknowledgements  KVP wishes to acknowledge Fondecyt Regular Project No 1211118, ANID and FIT, USS, Chile.

References Ali, F., Akbar, S., Sillanpaa, M., Younas, U., Ashraf, A., Pervaiz, M., Kausar, R., Ahmad, I., Alothman, A. A., & Ouladsmane, M. (2023). Recyclable Cu–Ag bimetallic nanocatalyst for radical scavenging, dyes removal and antimicrobial applications. Chemosphere, 313, 137321. https://doi.org/10.1016/J.CHEMOSPHERE.2022.137321 Al-Zubeidi, A., Stein, F., Flatebo, C., Rehbock, C., Jebeli, A. H., & S., F. Landes, C., Barcikowski, S., & Link, S. (2021). Single-particle hyperspectral imaging reveals kinetics of silver ion leaching from alloy nanoparticles. ACS Nano, 15(5), 8363–8375. https://doi.org/10.1021/ acsnano.0c10150 Arjun, P. N. J., Sankar, B., Shankar, K. V., Kulkarni, N. V., Sivasankaran, S., & Shankar, B. (2022). Silver and silver nanoparticles for the potential treatment of COVID-19: A review. Coatings, 12(11) MDPI. https://doi.org/10.3390/coatings12111679 AshaRani, P.  V., Sethu, S., Lim, H.  K., Balaji, G., Valiyaveettil, S., & Hande, M.  P. (2012). Differential regulation of intracellular factors mediating cell cycle, DNA repair and inflammation following exposure to silver nanoparticles in human cells. Genome Integrity, 3. https://doi. org/10.1186/2041-­9414-­3-­2 Auffan, M., Rose, J., Bottero, J. Y., Lowry, G. V., Jolivet, J. P., & Wiesner, M. R. (2009). Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nature Nanotechnology, 4(10), 634–641). Nature Publishing Group. https://doi.org/10.1038/ nnano.2009.242

14

V. Kokkarachedu et al.

Barillo, D. J., & Marx, D. E. (2014). Silver in medicine: A brief history BC 335 to present. Burns, 40(S1), S3–S8. https://doi.org/10.1016/J.BURNS.2014.09.009 Beus, M., Pongrac, I. M., Capjak, I., Ilić, K., Vrček, E., Ćurlin, M., Milić, M., Čermak, A. M. M., & Pavičić, I. (2023). Particle surface functionalization affects mechanism of endocytosis and adverse effects of silver nanoparticles in mammalian kidney cells. Journal of Applied Toxicology, 43(3), 416–430. https://doi.org/10.1002/jat.4392 Ferdous, Z., & Nemmar, A. (2020). Health impact of silver nanoparticles: A review of the biodistribution and toxicity following various routes of exposure. International Journal of Molecular Sciences, 21(7) MDPI AG. https://doi.org/10.3390/ijms21072375 Franzolin, M. R., Lopes, I. S., Courrol, D. d. S., de Souza Barreto, S., & Courrol, L. C. (2022). Synthesis, characterization, antimicrobial activity, and toxicity evaluation of aminolevulinic acid-silver and silver-iron nanoparticles for potential applications in agriculture. RSC Advances, 12(46), 30094–30103. https://doi.org/10.1039/d2ra05135d Ghetas, H. A., Abdel-Razek, N., Shakweer, M. S., Abotaleb, M. M., Ahamad Paray, B., Ali, S., Eldessouki, E. A., Dawood, M. A. O., & Khalil, R. H. (2022). Antimicrobial activity of chemically and biologically synthesized silver nanoparticles against some fish pathogens. Saudi Journal of Biological Sciences, 29(3), 1298–1305. https://doi.org/10.1016/J.SJBS.2021.11.015 Hosseini, M., Chin, A.  W. H., Williams, M.  D., Behzadinasab, S., Falkinham, J.  O., III, Poon, L.  L. M., & Ducker, W.  A. (2022). Transparent Anti-SARS-CoV-2 and Antibacterial Silver Oxide Coatings. ACS Applied Materials & Interfaces, 14(7), 8718–8727. https://doi. org/10.1021/acsami.1c20872 Hoyo, J., Ivanova, K., Torrent-Burgues, J., & Tzanov, T. (2020). Interaction of silver-lignin nanoparticles with mammalian mimetic membranes. Frontiers in Bioengineering and Biotechnology, 8. https://doi.org/10.3389/fbioe.2020.00439 Ibrahim, F. (2022). Synthesis of novel virus-like mesoporous silica-ZnO-Ag nanoparticles and quercetin synergize with NIR laser for omicron mutated covid-19 virus infectious diseases treatment. Advances in Nanoparticles, 11(01), 13–22. https://doi.org/10.4236/anp.2022.111002 Jeremiah, S. S., Miyakawa, K., Morita, T., Yamaoka, Y., & Ryo, A. (2020). Potent antiviral effect of silver nanoparticles on SARS-CoV-2. Biochemical and Biophysical Research Communications, 533(1), 195–200. https://doi.org/10.1016/J.BBRC.2020.09.018 Kabeerdass, N., Murugesan, K., Arumugam, N., Almansour, A. I., Kumar, R. S., Djearamane, S., Kumaravel, A. K., Velmurugan, P., Mohanavel, V., Kumar, S. S., Vijayanand, S., Padmanabhan, P., Gulyás, B., & Mathanmohun, M. (2022). Biomedical and textile applications of alternanthera sessilis leaf extract mediated synthesis of colloidal silver nanoparticle. Nanomaterials, 12(16). https://doi.org/10.3390/nano12162759 Kamaraj, C., Ragavendran, C., Manimaran, K., Sarvesh, S., Islam, A.  R. M.  T., & Malafaia, G. (2023). Green synthesis of silver nanoparticles from Cassia Auriculata: Targeting antibacterial, antioxidant activity, and evaluation of their possible effects on saltwater microcrustacean, Artemia Nauplii (non-target organism). Science of the Total Environment, 861. https://doi. org/10.1016/j.scitotenv.2022.160575 Kanikireddy, V., Varaprasad, K., Jayaramudu, T., Karthikeyan, C., & Sadiku, R. (2020). Carboxymethyl cellulose-based materials for infection control and wound healing: A review. International Journal of Biological Macromolecules, 164, 963–975. https://doi.org/10.1016/J. IJBIOMAC.2020.07.160 Karthikeyan, C., Varaprasad, K., Venugopal, S.  K., Shakila, S., Venkatraman, B.  R., & Sadiku, R. (2021). Biocidal (bacterial and cancer cells) activities of chitosan/CuO nanomaterial, synthesized via a green process. Carbohydrate Polymers, 259, 117762. https://doi.org/10.1016/J. CARBPOL.2021.117762 Liang, X., Luan, S., Yin, Z., He, M., He, C., Yin, L., Zou, Y., Yuan, Z., Li, L., Song, X., Lv, C., & Zhang, W. (2018). Recent advances in the medical use of silver complex. European Journal of Medicinal Chemistry, 157, 62–80. https://doi.org/10.1016/J.EJMECH.2018.07.057

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced…

15

Liu, W., Sun, Y., Cui, A., Xia, Y., Yan, Q., Song, Y., Wang, L., Shan, G., & Wang, X. (2023). Electrothermal sterilization and self-powered real-time respiratory monitoring of reusable mask based on Ag micro-mesh films. Nano Energy, 105, 107987. https://doi.org/10.1016/J. NANOEN.2022.107987 Maślana, K., Kędzierski, T., Żywicka, A., Zielińska, B., & Mijowska, E. (2022). Design of self-­ cleaning and self-disinfecting paper-shaped photocatalysts based on wood and eucalyptus derived cellulose fibers modified with gCN/Ag nanoparticles. Environmental Nanotechnology, Monitoring & Management, 17, 100656. https://doi.org/10.1016/J.ENMM.2022.100656 Medici, S., Peana, M., Nurchi, M., & V., & Antonietta Zoroddu, M. (2019). Medical uses of silver: History, myths, and scientific evidence. Journal of Medicinal Chemistry, 62(13), 5923–5943. https://doi.org/10.1021/acs.jmedchem.8b01439 Meister, T.  L., Fortmann, J., Breisch, M., Sengstock, C., Steinmann, E., Köller, M., Pfaender, S., & Ludwig, A. (2022). Nanoscale copper and silver thin film systems display differences in antiviral and antibacterial properties. Scientific Reports, 12(1). https://doi.org/10.1038/ s41598-­022-­11212-­w Mendes, C., Thirupathi, A., Corrêa, M. E. A. B., Gu, Y., & Silveira, P. C. L. (2022). The use of metallic nanoparticles in wound healing: New perspectives. International Journal of Molecular Sciences, 23(23). https://doi.org/10.3390/ijms232315376 Morones, J.  R., Elechiguerra, J.  L., Camacho, A., Holt, K., Kouri, J.  B., Ramírez, J.  T., & Yacaman, M. J. (2005). The bactericidal effect of silver nanoparticles. Nanotechnology, 16(10), 2346–2353. https://doi.org/10.1088/0957-­4484/16/10/059 Morozova, O.  V., Manuvera, V.  A., Grishchechkin, A.  E., Barinov, N.  A., Shevlyagina, N.  V., Zhukhovitsky, V. G., Lazarev, V. N., & Klinov, D. V. (2022). Targeting of silver cations, silver-­ cystine complexes, Ag nanoclusters, and nanoparticles towards SARS-CoV-2 RNA and recombinant virion proteins. Viruses, 14(5). https://doi.org/10.3390/v14050902 Nandhini, S.  N., Sisubalan, N., Vijayan, A., Karthikeyan, C., Gnanaraj, M., Gideon, D.  A. M., Jebastin, T., Varaprasad, K., & Sadiku, R. (2023). Recent advances in green synthesized nanoparticles for bactericidal and wound healing applications. Heliyon, 9(2), e13128. https:// doi.org/10.1016/J.HELIYON.2023.E13128 Naz, D., & ur Rahman, S., Aamir Aslam, M., & Muhammad, F. (2023). Immunotherapeutic and immunomodulatory potentials of antigen-antibody complex vaccines. Medical Hypotheses, 170, 111001. https://doi.org/10.1016/J.MEHY.2022.111001 Obata, K., Miyakawa, K., Takei, T., Wada, A., Hatayama, Y., Kato, H., Kimura, Y., Sekino, H., Katada, J., & Ryo, A. (2022). Prospective clinical evaluation of the diagnostic accuracy of a highly sensitive rapid antigen test using silver amplification technology for emerging SARS-­ CoV-­2 variants. Biomedicines, 10(11). https://doi.org/10.3390/biomedicines10112801 Pasparakis, G. (2022). Recent developments in the use of gold and silver nanoparticles in biomedicine. In Wiley interdisciplinary reviews: Nanomedicine and nanobiotechnology (Vol. 14, Issue 5). Wiley. https://doi.org/10.1002/wnan.1817 Peetsch, A., Greulich, C., Braun, D., Stroetges, C., Rehage, H., Siebers, B., Köller, M., & Epple, M. (2013). Silver-doped calcium phosphate nanoparticles: Synthesis, characterization, and toxic effects toward mammalian and prokaryotic cells. Colloids and Surfaces B: Biointerfaces, 102, 724–729. https://doi.org/10.1016/J.COLSURFB.2012.09.040 Pilaquinga, F., Morey, J., Torres, M., Seqqat, R., & Piña, M. de las N. (2021). Silver nanoparticles as a potential treatment against SARS-CoV-2: A review. In Wiley interdisciplinary reviews: Nanomedicine and nanobiotechnology (Vol. 13, Issue 5). Wiley. https://doi.org/10.1002/ wnan.1707 Puccetti, M., Donnadio, A., Ricci, M., Latterini, L., Quaglia, G., Pietrella, D., Di Michele, A., & Ambrogi, V. (2023). Alginate Ag/AgCl nanoparticles composite films for wound dressings with antibiofilm and antimicrobial activities. Journal of Functional Biomaterials, 14(2). https://doi.org/10.3390/jfb14020084

16

V. Kokkarachedu et al.

Raj, S., Trivedi, R., & Soni, V. (2021). Biogenic synthesis of silver nanoparticles, characterization and their applications—A review. Surfaces, 5(1), 67–90. https://doi.org/10.3390/ surfaces5010003 Ratan, Z. A., Mashrur, F. R., Chhoan, A. P., Shahriar, S. M., Haidere, M. F., Runa, N. J., Kim, S., Kweon, D. H., Hosseinzadeh, H., & Cho, J. Y. (2021). Silver nanoparticles as potential antiviral agents. Pharmaceutics, 13(12) MDPI. https://doi.org/10.3390/pharmaceutics13122034 Rodrigues, J. S. M., Rodrigues, A. M., & do Nascimento Souza, D., de Novais, E. R. P., Rodrigues, A. M., de Oliveira, G. C. A., & de Lima Ferreira Novais, A. (2021). DFT calculations to investigate silver ions as a virucide from SARS-CoV-2. Journal of Molecular Modeling, 27(11). https://doi.org/10.1007/s00894-­021-­04941-­8 Rozhin, A., Batasheva, S., Kruychkova, M., Cherednichenko, Y., Rozhina, E., & Fakhrullin, R. (2021). Biogenic silver nanoparticles: Synthesis and application as antibacterial and antifungal agents. Micromachines, 12(12) MDPI. https://doi.org/10.3390/mi12121480 Blevens, M. S., Pastrana, H. F., Mazzotta, H. C., & Su-Jung Tsai, C. (2021). Cloth face masks containing silver: Evaluating the Status. ACS Chemical Health & Safety, 28(3), 171–182. https:// doi.org/10.1021/acs.chas.1c00005 Said, M. M., Rehan, M., El-Sheikh, S. M., Zahran, M. K., Abdel-Aziz, M. S., Bechelany, M., & Barhoum, A. (2021). Multifunctional hydroxyapatite/silver nanoparticles/cotton gauze for antimicrobial and biomedical applications. Nanomaterials, 11(2), 1–25. https://doi.org/10.3390/ nano11020429 Salleh, A., Naomi, R., Utami, N. D., Mohammad, A. W., Mahmoudi, E., Mustafa, N., & Fauzi, M. B. (2020). The potential of silver nanoparticles for antiviral and antibacterial applications: A mechanism of action. Nanomaterials, 10(8), 1–20). MDPI AG. https://doi.org/10.3390/ nano10081566 Satheesh, V., Mohamed, J.  M. M., El-Sherbiny, M., Othman, G., Al-Serwi, R.  H., & Thilagar, S. (2022). Sunlight-assisted green synthesis of silver nanoparticles using Zizania latifolia extract: Toward antimicrobial applications. Biomass Conversion and Biorefinery. https://doi. org/10.1007/s13399-­022-­03363-­7 Sathiyaseelan, A., Saravanakumar, K., & Wang, M. H. (2022). Bimetallic silver-platinum (AgPt) nanoparticles and chitosan fabricated cotton gauze for enhanced antimicrobial and wound healing applications. International Journal of Biological Macromolecules, 220, 1556–1569. https://doi.org/10.1016/J.IJBIOMAC.2022.09.045 Sayes, C. M., Fortner, J. D., Guo, W., Lyon, D., Boyd, A. M., Ausman, K. D., Tao, Y. J., Sitharaman, B., Wilson, L.  J., Hughes, J.  B., West, J.  L., & Colvin, V.  L. (2004). The differential cytotoxicity of water-soluble fullerenes. Nano Letters, 4(10), 1881–1887. https://doi.org/10.1021/ nl0489586 Sharma, V. K., Yngard, R. A., & Lin, Y. (2009). Silver nanoparticles: Green synthesis and their antimicrobial activities. Advances in Colloid and Interface Science, 145(1–2), 83–96. https:// doi.org/10.1016/j.cis.2008.09.002 Siritapetawee, J., Limphirat, W., Pakawanit, P., & Phoovasawat, C. (2022). Application of Bacillus sp. protease in the fabrication of silver/silver chloride nanoparticles in solution and cotton gauze bandages. Biotechnology and Applied Biochemistry, 69(1), 20–29. https://doi. org/10.1002/bab.2075 Sondi, I., & Salopek-Sondi, B. (2004). Silver nanoparticles as antimicrobial agent: A case study on E. coli as a model for Gram-negative bacteria. Journal of Colloid and Interface Science, 275(1), 177–182. https://doi.org/10.1016/j.jcis.2004.02.012 Srinivasan, P., Sudhakar, S., Sengottaiyan, A., Subramani, P., Sudhakar, C., Manoharan, K., & Thiyagarajan, P. (2015). Green synthesis of silver nanoparticles using Cassia auriculata flower extract and its antibacterial activity. International Journal of Advanced Science and Engineering, 1(3) www.mahendrapublications.com Sudhisha, V., Saranya, K., Kalaiyarasan, M., & Rajendran, N. (2023). Silver nanoparticles doped poly(3, 4-ethylene dioxythiophene) on titania nanotubes for orthopaedic application. Applied Surface Science, 610, 155416. https://doi.org/10.1016/J.APSUSC.2022.155416

Silver Nanoparticles: A Promising Antimicrobial and Antiviral Material in Advanced…

17

Thiurunavukkarau, R., Shanmugam, S., Subramanian, K., Pandi, P., Muralitharan, G., Arokiarajan, M., Kasinathan, K., Sivaraj, A., Kalyanasundaram, R., AlOmar, S.  Y., & Shanmugam, V. (2022). Silver nanoparticles synthesized from the seaweed Sargassum polycystum and screening for their biological potential. Scientific Reports, 12(1). https://doi.org/10.1038/ s41598-­022-­18379-­2 Tiedemann, D., Taylor, U., Rehbock, C., Jakobi, J., Klein, S., Kues, W. A., Barcikowski, S., & Rath, D. (2014). Reprotoxicity of gold, silver, and gold-silver alloy nanoparticles on mammalian gametes. Analyst, 139(5), 931–942. https://doi.org/10.1039/c3an01463k Tripathi, D., Modi, A., Narayan, G., & Rai, S. P. (2019). Green and cost effective synthesis of silver nanoparticles from endangered medicinal plant Withania coagulans and their potential biomedical properties. Materials Science and Engineering C, 100, 152–164. https://doi.org/10.1016/j. msec.2019.02.113 Varaprasad, K., Jayaramudu, T., Kanikireddy, V., Toro, C., & Sadiku, E. R. (2020a). Alginate-based composite materials for wound dressing application: A mini review. Carbohydrate Polymers, 236, 116025. https://doi.org/10.1016/J.CARBPOL.2020.116025 Varaprasad, K., Karthikeyan, C., KanikiReddy, V., Núñez, D., Sadiku, E. R., & Briones, R. (2020b). Antibiotic nanomaterials. Antibiotic Materials in Healthcare, 1–10. https://doi.org/10.1016/ B978-­0-­12-­820054-­4.00001-­X Varaprasad, K., Karthikeyan, C., Yallapu, M.  M., & Sadiku, R. (2022). The significance of biomacromolecule alginate for the 3D printing of hydrogels for biomedical applications. International Journal of Biological Macromolecules, 212, 561–578. https://doi.org/10.1016/J. IJBIOMAC.2022.05.157 Varaprasad, K., Mohan, Y. M., Vimala, K., & Mohana Raju, K. (2011). Synthesis and characterization of hydrogel-silver nanoparticle-curcumin composites for wound dressing and antibacterial application. Journal of Applied Polymer Science, 121(2), 784–796. https://doi.org/10.1002/ app.33508 Varaprasad, K., Murali Mohan, Y., Ravindra, S., Narayana Reddy, N., Vimala, K., Monika, K., Sreedhar, B., & Mohana Raju, K. (2010). Hydrogel-silver nanoparticle composites: A new generation of antimicrobials. Journal of Applied Polymer Science, 115(2), 1199–1207. https:// doi.org/10.1002/app.31249 Wypij, M., Ostrowski, M., Piska, K., Wójcik-Pszczoła, K., Pękala, E., Rai, M., & Golińska, P. (2022). Novel antibacterial, cytotoxic and catalytic activities of silver nanoparticles synthesized from acidophilic actinobacterial SL19 with evidence for protein as coating biomolecule. Journal of Microbiology and Biotechnology, 32(9), 1195–1208. https://doi.org/10.4014/ jmb.2205.05006 Yang, P., & Wang, X. (2020). COVID-19: A new challenge for human beings. Cellular and Molecular Immunology, 17(5), 555–557). Springer Nature. https://doi.org/10.1038/ s41423-­020-­0407-­x Zou, Q., Gai, Y., Cai, Y., Gai, X., Xiong, S., Wei, N., Jiang, M., Chen, L., Liu, Y., & Gai, J. (2022). Eco-friendly chitosan@silver/plant fiber membranes for masks with thermal comfortability and self-sterilization. Cellulose, 29(10), 5711–5724. https://doi.org/10.1007/s10570-­022-­04582-­x

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications and Theranostic Potential Muniraj Gnanaraj, Natarajan Sisubalan, T. Jebastin, Arumugam Vijayan, T. Muneeshwaran, and R. Manikandan

Overviews Recent advances in infectious illnesses and the emergence of drug-resistant organisms have increased the need for efficient antibacterial and antiviral therapies. To fight infections, nanotechnology has emerged as a revolutionary field in the struggle against serious health concerns with new methods. Gold nanoparticles (AuNPs) have distinguished themselves among the wide variety of nanomaterials as intriguing candidates with distinct features that make them extremely promising for antibacterial and antiviral applications. AuNPs’ customizable size and shape, which enables researchers to tailor their properties to meet certain needs, is one of their main advantages. Due to their small size, they may effectively interact with viruses and bacteria at the cellular level, making them effective antimicrobial agents. In

M. Gnanaraj (*) · T. Jebastin Department of Biotechnology & Bioinformatics, Bishop Heber College (Autonomous), Trichy, Tamil Nadu, India N. Sisubalan Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand A. Vijayan Department of Microbiology, Faculty of Health and Medical Sciences, SRM Institute of Science and Technology, Tiruchirappalli, Tamil Nadu, India T. Muneeshwaran Lab of Toxicology, Department of Health Sciences, The Graduate School of Dong-A University, Busan, Republic of Korea R. Manikandan Padmavani Arts & Science College for Women, Opp. Periyar University, Salem, Tamil Nadu, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_2

19

20

M. Gnanaraj et al.

additiona, to improve their specificity and potency in pursuing infections, their surface is readily functionalizable with a variety of compounds, including antimicrobial peptides or antibodies. AuNPs are promising for prospective medicinal applications due to their good biocompatibility and low toxicity. When creating antimicrobial and antiviral medications, this is crucial because they must strike a careful balance between getting rid of germs and maintaining healthy cells and tissues. One advantageous quality that sets AuNPs apart from many other antimicrobial drugs, is their capacity to reduce negative effects on healthy cells. As possible therapeutic agents, AuNPs have shown particular promise in the context of the continuing coronavirus disease 2019 (COVID-19) epidemic. According to research, AuNPs can successfully engage with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins to prevent the virus from infecting host cells and causing COVID-19. Because of this trait, they are a strong candidate for the development of antiviral treatments for COVID-19 and other viral illnesses. AuNPs’ ability to fight infectious diseases is still a promising topic of research in the future. The range of uses  of these extraordinary nanomaterials is likely to increase as researchers continue to decipher the complex mechanics of their action and enhance their features. In addition, with the development of personalized medicine and targeted therapeutics, AuNPs show promise for revolutionizing the treatment of infectious diseases by providing customized strategies for unique patients. The development of antimicrobial and antiviral AuNPs has opened up new possibilities in the fight against infectious diseases. They are potent agents for battling viral and microbial illnesses thanks to their special qualities, adaptability, and low toxicity. These nanoparticles are anticipated to play a significant role in changing the face of infectious disease treatments as research advances and applications continue to develop, ushering in a new era of more effective and tailored therapeutics. Despite its many benefits, AuNP-based therapy is currently challenging to apply in clinical settings because research has shown that AuNPs have consequences and effects on health. There are currently limited research on nanotoxicity; it is challenging to evaluate the health of people and the environment. Therefore, more studies, both in vitro and in vivo, are needed to better understand the potential toxicity of gold nanoparticles (AuNPs). However, more research is still needed to overcome barriers and establish their efficacy and safety in many therapeutic scenarios. AuNPs may contribute significantly to the fight against infectious diseases and pave the way for cutting-edge, and improved treatment modalities.

Introduction One of the earliest metals to be discovered was gold; people undoubtedly found gold in streams and rivers worldwide, owing to its brightness and beauty (Rickard, 2015). The brilliant and valuable gold that has been beneficial to humans for millennia, remains a crucial component of today’s culture (Pradeep, 2009). Gold

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

21

continues to be a valuable resource, owing to its multiple uses in a range of industries as well as its historical importance as a symbol of wealth and power (Marsden & House, 2006). In recent years, bionanotechnology has developed as a promising topic with extensive applications in medicine, healthcare, agriculture, etc. (Thakur et al., 2018; Sivakami et al., 2021). Nanotechnology is an area of engineering and research that focuses on controlling and analyzing materials at the scale of 1–100 nanometres (Sisubalan et  al., 2018; Karthikeyan et  al., 2021). Recently, gold nanoparticles (AuNPs) have received much interest among the broad spectrum of nanoparticles being explored because of their unique surface plasmon resonance properties, facile synthesis, tunable sizes, and multifunctional abilities with well-­ characterized properties (Behzad et al., 2021; Bharadwaj et al., 2021; Mikhailova., 2021). AuNPs may be coupled with diverse molecules, such as proteins, dyes, medicines, antibodies, enzymes, and nucleic acids, to treat diseases (Tonelli et al., 2023). Several studies have been published on the uses of AuNPs as medication and gene delivery agents to treat various disorders (Zhang et  al., 2008; Mieszawska et  al. 2013; Kumar et al., 2011; Khan et al., 2016). In 1857, Faraday, first published an article on AuNPs. He thoroughly researched the AuNPs in a colloidal (dispersed) environment and recorded their optical characteristics, such as the light-scattering capabilities of suspended gold microparticles (Edwards & Thomas, 2007). In the late twentieth century, nanotechnology evolved and AuNPs are one of the most investigated nanomaterials that are used to answer healthcare and agricultural issues (Kannan et al., 2006; Mikhailova, 2021). Due to its particular physical and optical characteristics, it has various applications in many biological and environmental sectors (Bharadwaj et al., 2021). AuNPs may be generated using biological, physical, or chemical techniques (Herizchi et  al., 2016). AuNPs are manufactured chemically by the Turkevich technique (Turkevich et al. 1951; Hu et al., 2006), Brust-Schiffrin method (Brust et al., 1994), electrochemical approach (Huang et al., 2006), or seeded growth method (Siti et al., 2013). As an alternative to harsh chemicals employed in chemical synthesis operations, AuNPs are manufactured by biological means. The biosynthesis of AuNPs can be achieved using plants (Kamaraj et al., 2022; Suriyakala et al., 2022; Parthiban et al., 2023; Patil et al., 2023), bacteria (Sharma et al., 2012; Singh & Kundu 2014; Pourali et al., 2017; Cherian et al., 2022), fungi (Agnihotri et al., 2009; Castro-Longoria et al., 2011; Soltani Nejad et al., 2022), Algae (Naveena & Prakash, 2013; Rajan et al., 2015; Sharma et al., 2014a; b; Oza et al., 2012). As compared to other nanoparticle (NP) production, the biosynthesis of AuNPs is straightforward and sometimes does not need any rise in temperature or pressure. Instead of chemical reductants, electron beams, ultrasonication, or radiation is applied in physical approaches and involves solvent radiolysis, which forms diverse reactive oxygen species (ROS), which stimulates the synthesis of nanoparticles (Belloni et  al., 2020; Dey et  al., 2011; Dispenza et al., 2017) (Fig. 1). The size, shape, and surface functionality of the AuNPs may vary according to the approach employed for the synthesis (Hoshyar et al., 2016). This book chapter provides in-depth insights to the wide-range uses of AuNPs. It delves into various aspects of AuNPs, including antibacterial and antimicrobial mechanisms, toxicity effect on living cells, advantages and disadvantages, recent advancements, and prospects for the future.

22

M. Gnanaraj et al.

Fig. 1  Synthesis, characterization, and overview of AuNPs application

Advantages of AuNPs AuNPs offer several advantages over other nanoparticles. Here are a few key advantages: 1. Stability: AuNPs are known for their exceptional stability, both in terms of physical and chemical properties. They are less prone to oxidation and ­degradation, which makes them a good choice for long-term applications. They can also be functionalized with antibodies or DNA for targeted drug delivery or bioimaging applications (Dreaden et al., 2012; De Crozals et al., 2016; Marinoiu et al., 2020). 2. Biocompatibility and non-toxicity: AuNPs are generally considered to be biocompatible and non-toxic, which makes them an attractive candidate for use in biomedical applications, such as gene therapy, drug delivery, and imaging, without inducing harmful side effects on living organisms. Advancements in medical technology are possible because of their low toxicity and compatibility with biological systems (Connor et al., 2005; Lim et al., 2011; Singh et al., 2018). 3. Size and shape tunability: It is possible to synthesize AuNPs in various shapes and sizes, from spheres and rods to triangles and stars. Their proper-

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

23

ties can be tuned for particular applications such as their plasmonic resonance, catalytic activity, or targeting abilities (Sun & Xia, 2002; Paramasivam et al., 2017; Pearce et al., 2021). 4. High surface-to-volume ratio: The vast number of active sites for interactions with other molecules is made possible by the high surface-to-volume ratio of AuNPs. This feature is beneficial in sensing applications, which can detect even minute changes in the surroundings (Dreaden et  al., 2012; Ahmad et al., 2015; Kumar et al., 2015). 5. Stability and inertness: Under physiological conditions, AuNPs are stable and inert, which reduces their susceptibility to deterioration or oxidation. This guarantees their reliability in various applications (Dreaden et al., 2012; Berbec et al., 2018). 6. Optical properties: AuNPs have distinctive optical characteristics as a result of localized surface plasmon resonance (LSPR). Unique optical features produced by the LSPR have implications in sensing, imaging, and cancer therapy (Song et al., 2015; Do et al., 2020; Lee et al., 2018). 7. Surface functionalization: The surface of AuNPs can be easily functionalized with various biomolecules, enabling targeted drug delivery and specific binding (Jeong et  al., 2014; Austin et  al., 2014; Liu et  al., 2020b; Sibuyi et al., 2021). 8. Conductivity: Gold is an excellent conductor of electricity, and nanoscale structures can further improve the electrical conductivity of AuNPs. Applications involving electronics and optoelectronics depend on this feature (Hassan et al., 2022; He et al., 2022). 9. Catalytic activity: Due to their exceptional catalytic activity, AuNPs are useful in a wide range of chemical reactions and catalysis applications (Gou et al., 2020; Liu et al., 2020a; Biehler et al., 2023). 10. Photothermal conversion: AuNPs are useful in cancer therapy due to the ability of photothermal conversion (the ability to convert light energy into heat) (Yang et al., 2019; Guglielmelli et al., 2020; Gupta & Malviya, 2021). 11. Versatility: AuNPs find applications in a wide range of fields, including medicine, electronics, catalysis, and sensing, due to their unique ­combination of properties (Hammami & Alabdallah, 2021; Fan et  al., 2020; Khan et al., 2022). 12. Enhanced drug delivery: Drugs and medicinal agents can be transported via AuNPs. Due to their wide surface area, which facilitates effective medication loading, the cargo is better protected from deterioration and has higher bioavailability. In addition, site-specific drug delivery is improved by functionalizing AuNPs with targeting ligands, which also reduces off-target effects and increases therapy effectiveness (Dreaden et al., 2012; Bolanos et al., 2019; Waheed et al., 2022).

24

M. Gnanaraj et al.

Disadvantages of AuNPs 1. Cost and scalability: In comparison to other nanomaterials, the cost of producing precise sizes and shapes of AuNPs can be very high because gold is a precious metal. This expense may prevent them from being widely used, particularly in large-scale industrial applications (Sperling & Parak, 2010; Huang et al., 2007). 2. Potential toxicity at high concentrations: Although AuNPs are typically, thought to be safe at low quantities, there is rising worry regarding their possible toxicity at greater doses. Studies have demonstrated that AuNPs can cause cellular stress and inflammation when used in high dosages, calling for careful consideration of their dose-dependent effects (Zhang et  al., 2011; Sulaiman et  al., 2020; Sani et al., 2021). 3. Aggregation and stability: Since AuNPs have a high surface energy, they have a propensity to aggregate and form clusters over time. This aggregate may change their attributes, which may also prevent them from performing as intended. It can be challenging to achieve AuNPs’ long-term stability in varied situations. Aggregation problems must be reduced by using the right surface modification, stabilizing chemicals, or encapsulating techniques (Hassan et al., 2022).

Toxicity Effect (a Mechanism) on Living Cells The AuNPs have significant potential for a variety of applications, including medication administration, imaging diagnostics, and environmental cleanup. In addition to their distinctive physicochemical characteristics, AuNPs are gaining significant interest in several industries, including medicine, electronics, and catalysis (Giasuddin et al., 2012; Bharadwaj et al., 2021; Vodyashkin et al., 2021). They also offer a wide range of potential biological uses in gene therapy, cell imaging, photothermal and radiotherapy, biosensing, contrast agents for cancer, diagnostic tracers, and immobilized enzymes. In addition, they can be used as catalysts in the oxidation of carbon monoxide to purify water and hydrogen and to reduce pollution (Yah, 2013). The growing usage of synthetic nanoparticles in biology has led to the question of  whether they can be applied to human (Murthy, 2007; Gupta & Xie, 2018; Ahmed et al., 2021). Although bulk gold and other forms of metal are generally thought to be biocompatible, the special qualities of nanoparticles can add new traits and behaviours that may interact with biological systems in a different way. Concerns regarding the possible toxicity of AuNPs on living cells have been raised. For safe and responsible use, it is essential to comprehend the mechanisms

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

25

underlying the harmful effects of AuNPs. The level of toxicity of AuNPs depends on a variety of factors, such as size, shape, surface chemistry, surface charge, concentration, exposure route, and exposure period. So, studies are necessary to evaluate the possible toxic effects of AuNPs on normal cells or human cells (Hernandez-Diaz et al., 2021). Exposure to AuNPs may occur during development and synthesis, applications, such as direct intake into the system or injection, and waste disposal. Detecting exposure may be challenging when nanoparticles are inhaled from implants, absorbed through the skin, adhere to airborne and surface contaminants, or follow other routes of skin contact (Uboldi et  al., 2009: Yah, 2013; Byrne et al., 2010). From 1 nm to 500 nm, synthetic AuNPs are offered in a wide range of sizes and forms, including rods, spheres, tubes, wires, ribbons, plates, cubic, hexagonal, triangular, and tetrapods. In rare circumstances, the size and shape of AuNPs have affected their toxicity. Due to the fact that some of them have ligands on their surfaces, it was found that the toxicity of some AuNPs was size-dependent. However, others had a large surface area to volume ratio, which provided an avenue for more surface particle activity (Jennings & Strouse, 2007; Van Doren et al., 2011). Prior to any prospective therapeutic applications, it is essential to assess the in-­ vivo profile of nanomaterials (Fischer & Chan, 2007). Yah (2013) and Sani et al. (2021) described several investigations to assess the in  vivo and in  vitro toxicity (Tables 1 and 2). It is difficult to determine and generalize important aspects of AuNPs’ effects because the literature on their bioactivity depicts different experimental techniques. These prevent a proper assessment of the cytotoxicity of AuNPs and a judgment from being made. However, the toxicity of AuNPs depends on size, shape, and other coated particles. It is difficult to determine AuNPs’ effects with certainty because of the variety of experimental methods used in the literature on their bioactivity. The physicochemical characteristics and properties of AuNPs jointly affect the main toxicity. While some research refutes this, others support non-toxicity. For a thorough inference, more study is required to characterize NPs and track changes after exposure to biological media (Sani et al., 2021). The extensive use of AuNPs has prompted concerns regarding their possible toxicity to microorganisms, though. To determine the safety of their applications and direct the development of antimicrobial techniques, it is essential to understand the interactions between AuNPs and microorganisms, such as bacteria, fungi, and viruses (Duncan, 2011). Recent investigations have shown that a number of common processes are principally responsible for the antibacterial effects of nanoparticles (NPs). Nanoparticles utilized their antimicrobial activities through several mechanisms, including (1) cell membrane interaction, (2) prevention of biofilm generation, (3) induction of ROS, and (4) interaction with DNA or proteins (Fig. 2) (Baptista et al., 2018; Singh et al., 2018; Rosli et al., 2021).

26

M. Gnanaraj et al.

Table 1  In-vivo toxicity studies of AuNPs Organism Wistar rats

Particle AuNPs

Foetal organs AuNPs Pregnant AuNPs C57BL/6 mice Female and AuNPs male mice Zebrafish embryo Rats Mice

BALB/c mice Mice Male WU Wistar rats

AuNPs (functionalized with TMATeAuNPs) AuNPs AuNSs on GSNPs (Gelatin/silica hybrid nanoparticles) AuNPs PEG-coated AuNPs AuNPs

Female mice Mice (ddy)

AuNPs AuNPs

Male Wistar rats Wistar rats

AuNPs

Effects Traces of AuNPs in the kidney, spleen, liver, intestine, urine, and feces. Smaller NPs induced greater effects on DNA damage No indication of toxicity in the foetus and placenta Noncrossing of maternal-foetal barrier Liver and the kidney damage whose effects were sex–dependent Delay in development of eyes and pigmentation

Changes in gene expression Lungs, the kidney haemorrhage, lymphocytic infiltration, and inflammatory response Apoptosis and inflammation of the liver tissue Liver damage Large particles of spherical AuNPs were observed in the blood, spleen and liver while smaller particles were seen in the spleen, blood, thymus, lungs, liver, kidney, testis, heart, and brain Spherical AuNPs in the liver and macrophages AuNPs of all sizes were noticed in the spleen, liver, and lungs AuNPs persist and accumulate in the spleen and liver

Citrate-coated AuNPs Accumulate in the neurons, liver, spleen, kidney and cross the blood-brain barrier; no toxicity Rats PEG-coated AuNPs Accumulation in the spleen and liver Mice PEG-coated AuNPs Apoptosis and acute inflammation Rats PEG-coated AuNPs ROS-induced cytotoxicity that is size-dependent Rats AuNPs Distribution of AuNPs was observed in the testis, liver, and kidney. However, no effects on the testis, whereas mild changes were noticed in the kidney and liver sections Affects the kidney function and produces toxicity Mice GSH (glutathione)and BSA (Bovine serum albumin)coated AuNCs (Gold Nanoclusters) Broiler chicken AuNPs Caused recognizable oxidative damage to blood, histopathological changes, up-regulation of IL-6, expression of Nrf2 gene, fragmentation of DNA, a significant decrease in antibody titre against avian influenza (AI) and Newcastle disease (ND) Mice AuNPs Damage to the neuronal system (continued)

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

27

Table 1 (continued) Organism Male CD1 mice Drosophila melanogaster Drosophila melanogaster Mice Mice

Mice Mice Female mice Daphnia magna D. magna Moina macrocopa Trachipterus arcticus

Particle Effects Functionalized Accumulation at various parts of the brain AuNPs Citrate-capped AuNPs Caused transmissible mutagenic effects Citrate-capped AuNPs Sharp decline in fertility and life span, presence of DNA fragments, and strong over-expression of stress proteins Citrate-capped AuNPs Greatest toxicity and affecting organ index Produced no effect on normal growth AuNPs capped with BSA and HSePEGeCOOH AuNPs Induced reduction in RBC, spleen index, and body weight Naked colloidal Caused loss of weight and appetite. However, smaller AuNPs AuNPs did not produce any sickness AuNHsd Complete survival was evident across all concentrations HAuCl4 Half-maximal inhibitory concentration (IC50) was reported as 2 mg/L after 48 h HAuCl4 IC50 was reported as 0.64 mg/L after 48 h HAuCl4 IC50 was reported as 0.62 mg/L after 48 h IC50 was 14.4 mg/L after 96 h

Adapted from Sani et al., (2021)

Antimicrobial Mechanisms of AuNPs Cell Membrane Interaction Bacteria’s cell walls and cell membranes serve as their first line of defence. These essential elements serve critical functions as a protective barrier, assisting bacteria in maintaining their shape and providing assistance and defence against the outside environment (Liu et  al., 2015). The small size and large surface area of AuNPs enable them to interact with the cell membrane of microorganisms (Fig. 2). AuNPs may disrupt the integrity of the microbial cell membrane, making it more permeable and potentially leading to membrane rupture. Cell death is the ultimate effect of this destabilization (Mahalingam et al., 2015). Gram-positive bacteria are more sensitive to the antibacterial properties of AuNPs than Gram-negative bacteria. This variation in susceptibility can be linked to the structural differences in the cell walls of each organism. The complex cell wall of Gram-negative bacteria is made up of phospholipids, lipoproteins, and lipopolysaccharides. This mixture creates a strong barrier that only macromolecules can pass through, protecting the cell membrane from its surroundings. As a result,

M. Gnanaraj et al.

28 Table 2  In vitro toxicity studies involving AuNPs Organism Human colorectal adenocarcinoma cells (HT29)

Particle AuNPs

Effects Significant reduction in viability of cells. However, no genotoxic effects Hepatoblastoma cells (HepG2) AuNPs Indicated tails moment similar to those from positive control in which cells were exposed to hydrogen peroxide Hepatoblastoma cells (HepG2) AuNPs AuNPs do not change the concentration of inflammatory markers when compared to the control Osteosarcoma cells (MG63) AuNPs Low long-term toxicity BALB/c 3 T3 fibroblast cells Coated and uncoated DNA damage results via spherical AuNPs indirect oxidative stress Epithelial cells of airways AuNPs Elevation of lipid peroxidase as well as DNA damage and cytotoxicity Mouse lymphoma cells AuNPs No damage to the DNA at (L5178Y) 60 nm, but there was damage at 100 nm Human lung fibroblast cells AuNPs capped with GNPC Slight hepatotoxic and (MRC-5) and GNPB nephrotoxic Human lung fibroblast cells AuNPs High lipid peroxidation, (MRC-5) up-regulation of antioxidants, expressions of protein and gene of stress response Rat liver AuNPs Yield a great lipid peroxidation Human leukaemia (HL-60) and AuNPs Cytotoxicity effects associated hepatoma (HepG2) cell lines with reduction of GSH and increase in ROS Mouse embryonic fibroblast cells Plain and GSH-capped Produce more reactive oxygen (3 T3) AuNPs species than plain AuNPs Cytotoxic Henrietta lacks cells (HeLa) and Citrate-capped AuNPs pro-monocytic, human histiocytic lymphoma cells (U937) AuNPs capped with either In vitro cytotoxicity and Hepatoblastoma cells (HepG2) genotoxicity effects at low sodium citrate or and peripheral blood concentrations polyamidoamine mononuclear cells (PBMC) dendrimers Mouse embryonic fibroblasts AuNPs uncoated and Oxidative stress was reflected (Balb/3T3) cells coated with hyaluronic acid in DNA damage but with reduced cytotoxicity Neuronal cell line (C17.2) and AuNPs Caused oxidative stress by cell pheochromocytoma cells (PC12) viability and deformations of actin and tubulin (continued)

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

29

Table 2 (continued) Organism Mouse embryonic fibroblast (Balb/3T3) cells Human lung fibroblast cells (MRC-5) Human keratinocyte cell line HaCaT Vero, human lung fibroblast cells (MRC-5), and NIH/Swiss fibroblast cells (NIH/3T3 cells) Granulose cells of the ovary

Particle Citrate-stabilized AuNPs AuNPs AuNPs AuNPs

AuNPs

Human spermatozoa AuNPs Adenocarcinoma human alveolar AuNPs coated with serum basal epithelial cells (A549) proteins Human foetal lung fibroblasts

AuNPs

Adenocarcinoma human alveolar AuNPs basal epithelial cells (A549) Human liver cell lines (HL7702 AuNPs cells)

MG63 osteoblast-like cells AuNPs Adenocarcinoma human alveolar AuNPs basal epithelial cells (A549) Polymer-modified AuNPs Adenocarcinoma human alveolar AuNPs basal epithelial cells (A549) AGS, A549, NIH3T3, PK-15, AuNPs and Vero cells

Effects Cytotoxicity by disruption of actin cytoskeleton Autophagy and oxidative stress Cell death by apoptosis and necrosis Reduction in growth and was related to apoptosis and autophagy Induced an elevation in oestrogen accumulation Affects viability and motility Intrinsic and extrinsic apoptotic pathways reflected in cell damage Destabilized the expression of 19 genes in the cells Assumed circular shape because of the induced stress Early decrease in cytosolic GSH, depolarization of mitochondrial transmembrane potential, and subsequently, apoptosis Cell death Cytotoxicity by substantial changes in nuclear morphology and nuclear condensation Hemocompatibility with human RBCs An inflammatory response

Vero cells

AuNPs

NIH/Swiss fibroblast cells (NIH3T3) Human lung fibroblast cells (MRC-5) Breast cells (MDA-MB-231)

AuNPs

Suppression of growth of cells in a dose-dependent manner by delay of cell cycle and induction of apoptosis Reduction in cell growth and related to apoptosis Autophagy

AuNPs

DNA damage

AuNPs

Reduction in proliferation (continued)

30

M. Gnanaraj et al.

Table 2 (continued) Organism Human cell lines

Human cells Chinese hamster ovary cells (CHO), human bronchial epithelial cells (BEAS-2B), and human embryonic kidney (HEK293) cells Henrietta lacks cells (HeLa) Lung adenocarcinoma (A549) and Vero cells Cancer coli-2 cells (Caco-2) Vero cells Tumour ascites and normal peritoneal cells Henrietta lacks cells (HeLa) Human embryonic kidney cells (HEK293) Human carcinoma lung cell Human liver carcinoma cell

Particle AuNRs (gold nanorods) coated with methoxypolyethylene glycol thiol AuNPs

Effects Alterations in viability of cells except for thyroid papillary carcinoma cells

Citrate-stabilized AuNPs

Little or no immunotoxic, cytotoxic, and genotoxic effects Exert higher toxicity

AuNPs AuNPs conjugate

No indication of cytotoxicity No toxicity

AuNPs

Did not produce acute cytotoxicity No toxicological effects No morphological changes and cell death No toxicity effects

Porphyran-reduced AuNPs Functionalized AuNPs Silica-coated AuNRs and glucose-capped AuNPs Phosphine-stabilized and thiol-stabilized AuNPs Citrate-capped AuNPs Citrate-capped AuNPs

Modified the gene expression and had no toxicity Induce toxicity No toxicity effects

Adapted from Sani et al., (2021)

breaking through this barrier and properly exerting their antibacterial function is more difficult for AuNPs (Suganya et al., 2015; Gupta et al., 2019; Skladanowski et al., 2017; Alexander et al., 2018; Nishanthi et al., 2019). Gram-positive bacteria have cell walls that are distinguished by a thick layer of peptidoglycan and teichoic acid and include lots of holes. Foreign compounds, such as AuNPs, can easily enter these pores. Once enters inside, the AuNPs have the potential to rupture membranes, allowing cytoplasmic components to flow out and eventually inducing death in Gram-positive bacteria (Skladanowski et  al., 2017; Nishanthi et al., 2019). To protect against antibiotics, bacteria create biofilms by sticking to one another on surfaces and are involved in the production of extracellular polymeric substances (EPS), which makes the bacteria resistant to a variety of antibiotics. However, studies suggest that AuNPs can prevent the growth of biofilms by entering the EPS matrix and killing the microbes (Fig. 2) (Pelgrift & Friedman, 2013).

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

31

Fig. 2  The illustration shows the various antibacterial strategies used by AuNPs to combat bacteria. (Recreated from Sharmin et al., 2021)

Induction of Reactive Oxygen Species (ROS) The nanosize of nanoparticle complexes enables penetration into bacterial cells, disturbing gene expression and efflux pumps, and triggering the generation of ROS within microorganisms. The elevated ROS levels can cause oxidative stress (Fig. 2), leading to cellular damage and disruption of essential biomolecules which finally kill the pathogenic microbial cell (Cui et  al., 2012; Lee & Lee, 2018; Ahmad et al., 2022).

Interaction with DNA or Proteins AuNPs can penetrate into microbial cells and interact with their genetic material, causing DNA damage and potential genetic mutations (Singh et  al., 2009; Shah et al., 2014). The production of ROS is directly related to the interactions between DNA and bacterial cells. Bacterial cells overproduce ROS when exposed to NPs, which causes oxidative DNA damage (Mortezaee et al., 2019). ROS mainly includes hydroxyl ions, peroxide ions, superoxide anions, singlet oxygen, and hypochlorous acids. Studies have shown that NPs can cause DNA damage by preventing DNA replication in cells after diffusing through their cell membranes, which results in apoptosis (Fig.  2). In addition, by creating an excess of ROS, nanoparticles may hinder a cell’s capacity to repair DNA damage (Rowe et  al., 2008; Ahmad et al., 2022).

32

M. Gnanaraj et al.

AuNPs directly interact with the cell wall or membrane of bacteria, which prevents biofilm development and is thought to be the cause of their antibacterial effectiveness. Furthermore, AuNPs demonstrate potent antibacterial activities by producing innate and adaptive host immunological responses, harmful ROS, and intracellular consequences such as enzyme malfunction, DNA damage, and protein degradation. AuNPs are powerful agents in the fight against microbial diseases due to these complex mechanisms.

Antiviral Mechanism of AuNPs The creation of innovative antiviral techniques is necessary because viral infections pose serious risks to world health. Due to their distinct physicochemical features, AuNPs have drawn a lot of interest as a possible antiviral drug. To fully utilize their potential in battling viral infections, it is essential to comprehend the many processes behind their antiviral activity. The AuNPs have multiple antiviral capabilities, including viral entry inhibition, disruption of viral structures, interference with viral replication, and modulation of the host immune response (Fig. 3). AuNPs are versatile agents in the battle against viral diseases because of their size and shape. Smaller NPs have been found to more easily reach the virus genome after penetrating into the virus-host cell and stop the viral replication by blocking cellular factor and viral factor mechanisms in the genome.

Fig. 3  Antiviral activity of AuNPs. (Recreated from Sharmin et al., 2021)

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

33

Inhibition of Viral Attachment and Entry Inhibiting viral entrance into host cells is one of the main mechanisms behind the antiviral activity of AuNPs. The first stage of a viral infection cycle is known as viral entry, during which the virus latches to certain receptors on the surface of the host cell and enters the cell. It has been demonstrated that by binding with viral surface proteins or glycoproteins (Reina et  al., 2020), AuNPs can obstruct this process (Fig. 3). The ability of AuNPs to prevent virus entry into host cells through a special mechanism has been successfully demonstrated by researchers. They accomplish this by interacting with the viral surface protein haemagglutinin. The disulphide linkages in the haemagglutinin glycoprotein are oxidized by AuNPs, rendering the protein inactive. As a result, the virus and host cell cannot successfully fuse their membranes (Thompson et al., 2004; Budhadev et al., 2020; Melendez-Villanueva et al., 2019). AuNPs successfully restrict viral infection of host cells by obstructing viral entry, hence limiting viral dissemination and reproduction within the host. The progression of viral diseases may be stopped by this prevention of viral entry, which is especially useful in preventing the onset of infection in the beginning stages (Melendez-Villanueva et al., 2019). The antiviral activity of AuNPs through viral entry inhibition has been investigated against a variety of viruses, including non-enveloped viruses such as rotavirus and human papillomavirus (HPV) as well as enveloped viruses such as influenza virus, human immunodeficiency virus (HIV), and herpes simplex virus (HSV), coronavirus (COVID-19) (Cagno et  al., 2018; Rosli et  al., 2021: Yasamineh et al., 2022). The efficiency of AuNPs in preventing viral entrance is also greatly influenced by their size and surface characteristics (Vonnemann et al., 2014; Chen & Liang, 2020). Smaller AuNPs have enhanced antiviral efficacy and better cellular absorption (Sibuyi et  al., 2021). AuNPs’ capacity to obstruct viral entry can also be improved by surface functionalization with ligands that specifically target viral receptors (Baram-Pinto et al., 2010).

Disruption of Viral Structures The ability of gold nanoparticles (AuNPs) to denature viral structures is a critical factor underlying their antiviral actions. Viral components, especially the viral envelope in enveloped viruses or the viral capsid in non-enveloped viruses, can interact with AuNPs, causing structural changes that leave the virus inactive or less contagious. When it comes to viruses that have an envelope, AuNPs may interact with the lipid bilayer, leading to the destabilization and rupture of the envelope (Fig.  3). During the viral entrance phase, this disruption stops the virus from merging with the host cell membrane. The virus can no longer introduce its genetic material into the host cell and start viral replication as a result (Tatur et al., 2013; Steinmetz & Manchester, 2011; Lin et al., 2021; Ghosal, 2023).

34

M. Gnanaraj et al.

AuNPs can target the viral capsid proteins, which are in charge of guarding the genetic material of non-enveloped viruses. AuNPs can cause structural changes that compromise the integrity of the viral particle by interacting with these capsid proteins. The virus cannot effectively transport its genetic material into host cells as a result of this damage to the viral capsid (Tatur et al., 2013; Du et al., 2015; Monroe et al., 2022). AuNPs may also obstruct the maturation and assembly of freshly generated viral particles. AuNPs can interfere with the normal generation of infectious virions, resulting in the production of non-functional viral particles. They do this by interacting with viral structural proteins or enzymes involved in viral assembly (Medhi et al., 2020).

Interference with Viral Replication Interfering with viral replication is a crucial additional way that AuNPs exert their antiviral action. A virus that enters a cell successfully, must go through reproduction in order to create new viral particles that can infect additional cells. The disruption of this replication mechanism by AuNPs prevents the virus from multiplying and spreading within the host. AuNPs can interact with viral nucleic acids (DNA or RNA) or viral enzymes necessary for viral replication once inside the host cell (Fig. 3). The replication machinery of the virus can be interfered with by AuNPs, resulting in the creation of ineffective or incomplete viral particles (Rafiei et  al., 2015; Ghaffari et al., 2019; Farzin et al., 2020; Paradowska et al., 2021).

Recent Studies on Antimicrobial and Antiviral Applications AuNPs have  recently, drawn considerable  attention due to their potential use in treating viral and microbial illnesses. AuNPs are attractive prospects for a variety of biomedical applications due to their distinctive physicochemical characteristics, which include their customizable size, shape, and surface functionalization. A few recent studies have been listed later. Hryniewicz et al., (2022) developed a promising biosensor for COVID-19 immunodiagnostic based on polypyrrole (PPy), synthesized in both globular and nanotubular (NT) shapes, and AuNPs. AuNPs and carboxy methyl cellulose (CMC) were combined to successfully create a nanocomposite (CMC-AuNPs) with diameters ranging from 10 to 90 nm. The nanocomposite demonstrated modest antibacterial activity against Staphylococcus aureus and Bacillus cereus with minimum inhibitory concentrations (MICs) of 25 g/mL. CMC-AuNPs demonstrated greater antibacterial activity against Klebsiella oxytoca and Escherichia coli with MICs of 50  g/mL and 100  g/mL, respectively. In addition, CMC-AuNPs showed notable antifungal activity against Aspergillus terreus, Candida albicans, Aspergillus niger,

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

35

and Aspergillus fumigatus. CMC-AuNPs demonstrated a potent cytotoxic effect on breast cancer cells, causing necrosis and death by up-regulating caspase-8 and -9 activities and down-regulating VEGFR-2 levels. These results indicate that CMC-­ AuNPs have the potential to be effective candidates for antibacterial and anticancer applications (Doghish et al., 2022). The marine fungus Alternaria chlamydospora has been used successfully to create AuNPs on a global scale for the first time. A dose-dependent response of the AuNPs was seen in the antioxidant, antibacterial, and cytotoxicity assays. Notably, their antioxidant activity was demonstrated by the discovery of the half-maximal inhibitory concentration (IC50) value for the suppression of DPPH radicals. In addition, the AuNPs’ antibacterial abilities were tested against four different bacterial diseases, and the results showed an inhibitory effect with rising nanomaterial concentrations. The cytotoxicity of the AuNPs was evaluated in the context of their anticancer potential against A549 cell lines using the MTT (3-­[4,5-­dimethylthiazol-­­ 2-­yl]-­2,5 diphenyl tetrazolium bromide) assay, confirming their capacity to manifest an anti-cancer effect (Ameen et al., 2023). The accurate creation of photocatalysts with the required qualities is demonstrated in a new case of materials-gene engineering. The CO2 conversion pathways over AuNPs loaded TiO2 photocatalysts are controlled by the phase-doping strategy, which is based on theoretical calculations. The face-centred cubic (fcc) phase AuNPs successfully incorporate stable twinning crystal planes, releasing the CO2-­ to-­CO conversion’s thermodynamic bottleneck. According to the findings, CO production is increased by over 40 times with twinning (110) and (100) facets on AuNPs, which also achieve close-to-unity CO selectivity. This improvement results from a favourable change in the energetics of surface reactive sites at the twinned stacking defect, which lowers the energies of CO reaction and desorption (Huang et al., 2022). According to the principles of green chemistry, Hosny et  al., (2022a) demonstrated the methods to produce stable AuNPs quickly, cheaply, and safely for the environment. They accomplished it by using an aqueous extract of T. capensis leaves. T. capensis-AuNPs demonstrated excellent effectiveness in inhibiting the growth and proliferation of human breast cancer cells (MCF7 cell line) with an IC50 value of 9.6 g/mL. Furthermore, T. capensis-AuNPs and T. capensis extract demonstrated strong antioxidant effectiveness with DPPH scavenging percentages of 70.73% and 85.62%, respectively. Quick and environmentally friendly stable AuNPs were produced by utilizing an aqueous extract of Ziziphus spina-christi leaves. After five regeneration cycles, Zi-AuNPs (Ziziphus spina christi leaves extracts stabilized gold nanoparticles) displayed high recycling capacity (69.2%) and effective photodegradation efficiency (81.14%) against toxic pollutants such as malachite green. The cytotoxicity test using the MTT assay demonstrated strong anticancer efficacy for both Zi-AuNPs and Z. spina-christi extract against human breast cancer cells (MCF7 cell line) with IC50 values of 48 and 40.25 g/mL, respectively. Outstanding antioxidant efficacy was observed, with Zi-AuNPs showing a DPPH (2,2-diphenyl-1-picrylhydrazyl) removal percentage of 67.5%, and Z. spina-christi extract achieving an impressive 92.34% (Hosny et al., 2022b).

36

M. Gnanaraj et al.

To test their photocatalytic breakdown of colours, AuNPs were produced by  using Gelidiella acerosa and had antibacterial action against S. aureus. Commercially significant dyes are degraded by AuNPs, particularly methylene blue and rhodamine B (Subbulakshmi et al., 2023). AuNPs and drug-containing, mPEG-conjugated curcumin (mPEG-CUR), self-­ assembled NPs (mPEG-CUR@Au) have been produced as an excellent radiosensitizer with enhanced tumour retention. Through synchronous chemoradiotherapy, mPEG-CUR@Au NPs greatly increase the effectiveness of cancer therapy in a mouse model of breast cancer by acting as both a radiosensitizer and a drug carrier (Nosrati et al., 2022). The Egyptian propolis extract is able to successfully synthesize ultra-small, highly pure, and stable AuNPs (average diameter of 7.8  nm). The synthesized AuNPs were found to have strong antibacterial and antimycobacterial properties in in vitro. In addition, experiments on human cancer cell lines showed that they had a considerable inhibitory effect on the growth of cancer cells, leading to death via reactive oxygen species. Studies on the acute toxicity and in vivo bio-distribution of ultra-small AuNPs in male albino rats at doses of 10 and 100 mg/kg revealed that they displayed non-toxic, especially at the lower dose (Aljohani et al., 2022). To successfully remove formaldehyde (HCHO) from indoor air, a novel TiO2 co-­loaded with platinum and AuNPs have been developed by Ye et al., 2022.

Future Use AuNPs have attracted a lot of interest in the field of nanotechnology due to their distinctive physical, chemical, and optical features, and their potential applications in the future across numerous fields are quite promising. AuNPs are flexible tools with applications across numerous scientific and technical sectors because of their size- and shape-dependent characteristics. They are appealing for practical use in nanomedicine due to the variety of their anti-microbiological processes, which have shown promising antibacterial properties. AuNPs are anticipated to play a transformative role in personalized medicine, cancer therapy, diagnostics, imaging, gene editing, and environmental cleanup. They can also solve issues in a range of industries due to their adaptability and agility, opening the door to creative applications outside the biological field. Even though AuNPs have a lot of potential, it is important to take into account their large-scale uses in order to comprehend their biological impacts at the cellular and subcellular levels and to handle any potential environmental ramifications. Here, we explore some promising potential applications for AuNPs. 1. Biomedical imaging and targeted therapy: The effectiveness of AuNPs in medical imaging procedures including computed tomography (CT) scans and photoacoustic imaging has been already established. Deeper tissue penetration and high-resolution imaging are made

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

2.

3.

4.

5.

37

possible by their capacity to substantially absorb and scatter light in the near-­ infrared region. AuNPs have potential in drug delivery systems in addition to their use in imaging and targeted therapy. They can be functionalized with different ligands to deliver medications precisely to their target areas, enhancing therapeutic effectiveness. AuNPs may be used in sophisticated drug delivery systems in the future to get beyond biological restrictions and deliver therapies to areas that were not previously reachable. Cancer treatment: Researchers are investigating the potential of AuNPs in the treatment of cancer through methods including photothermal therapy and radiotherapy enhancement. AuNPs can effectively target and kill cancer cells by generating localized heat or enhancing radiation effects when exposed to light or ionizing radiation, respectively. The design of nanoparticles may be improved in the future for improved tumour accumulation and regulated release of therapeutic payloads. Environmental remediation: AuNPs have catalytic capabilities that make them useful for cleaning up the environment. They can be utilized for photocatalysis or electrocatalysis to destroy contaminants, such as organic dyes and insecticides. Future applications could include the production of AuNP-based systems to combat new contaminants and enhance the quality of the air and water. Electronics and optoelectronics: AuNPs have generated interest in the nanoelectronics industry because of their remarkable electrical conductivity and plasmonic qualities. AuNPs are ­prospective candidates for the next generation of electronics and optoelectronics due to their exceptional electrical and optical capabilities. It is possible to make circuits that operate more quickly and efficiently by using them as the building blocks for nanoscale electronic devices. Due to their distinct electrical behaviour at the nanoscale, AuNPs may be used in flexible displays, sophisticated sensors, and possibly quantum computing devices in the future. Energy harvesting and storage: AuNPs can help to create effective systems for energy harvesting and storage. Their catalytic abilities could increase fuel cells and energy storage devices, while their plasmonic features could improve light absorption in solar cells. Future research might concentrate on incorporating AuNPs into hybrid systems that maximize the efficiency of energy conversion and storage.

AuNPs have an extremely bright future because of their potential use in a wide range of scientific and technical fields. As researchers continue to elucidate their properties and investigate cutting-edge synthesis methodologies, AuNPs are poised to change the landscape of medicine, electronics, environmental conservation, energy production, and more. The prospect of using AuNPs to their full capacity is boundless with interdisciplinary cooperation and focused efforts, providing ground-­ breaking solutions to some of the most significant issues of today’s world.

38

M. Gnanaraj et al.

Conclusion Research in the ground-breaking field of antimicrobial and antiviral AuNPs have enormous promise for eradicating infectious illnesses and revolutionizing contemporary medicine. The implementation of AuNP-based therapy in clinical settings still faces difficulties despite the many advantages. Concerns regarding biocompatibility, toxicity, long-term consequences, and industrial manufacturing require additional study, because studies so far indicate the health impacts and implications of AuNPs. Nanotoxicity studies are currently limited, making it difficult to assess the health state of both humans and the environment. More in vitro and in vivo AuNPs and gold nanoparticles toxicity research is therefore needed to enhance the scarce and contentious evidence already available (whether harmful or non-toxic). In conclusion, antibacterial and antiviral AuNPs hold the key to reducing the burden of infectious diseases globally by providing fresh opportunities for targeted therapeutics, precision medicine, and sustainable methods of providing healthcare. AuNPs have the potential to revolutionize medicine if it is established that they are non-toxic. Offering inventive ways to combat infections and improve human health through more scientific study and collaborative efforts between researchers, clinicians, and regulatory agencies are needed. Conflict of Interest  There is no conflict of interest to declare.

References Agnihotri, M., Joshi, S., Kumar, A. R., Zinjarde, S., & Kulkarni, S. (2009). Biosynthesis of gold nanoparticles by the tropical marine yeast Yarrowia lipolytica NCIM 3589. Materials Letters, 63(15), 1231–1234. Ahmad, R., Griffete, N., Lamouri, A., Felidj, N., Chehimi, M.  M., & Mangeney, C. (2015). Nanocomposites of gold nanoparticles@ molecularly imprinted polymers: Chemistry, processing, and applications in sensors. Chemistry of Materials, 27(16), 5464–5478. Ahmad, N., Muhammad, J., Khan, K., Ali, W., Fazal, H., Ali, M., et al. (2022). Silver and gold nanoparticles induced differential antimicrobial potential in calli cultures of Prunella vulgaris. BMC Chemistry, 16(1), 20. Ahmed, H.  M., Roy, A., Wahab, M., Ahmed, M., Othman-Qadir, G., Elesawy, B.  H., et  al. (2021). Applications of nanomaterials in agrifood and pharmaceutical industry. Journal of Nanomaterials, 2021, 1–10. Alexander, J.  L., Thompson, Z., & Cowan, J.  A. (2018). Antimicrobial metallopeptides. ACS Chemical Biology, 13(4), 844–853. Aljohani, F. S., Hamed, M. T., Bakr, B. A., Shahin, Y. H., Abu-Serie, M. M., Awaad, A. K., et al. (2022). In vivo bio-distribution and acute toxicity evaluation of greenly synthesized ultra-small gold nanoparticles with different biological activities. Scientific Reports, 12(1), 6269. Ameen, F., Al-Maary, K.  S., Almansob, A., & AlNadhari, S. (2023). Antioxidant, antibacterial and anticancer efficacy of Alternaria chlamydospora-mediated gold nanoparticles. Applied Nanoscience, 13(3), 2233–2240. Austin, L. A., Mackey, M. A., Dreaden, E. C., & El-Sayed, M. A. (2014). The optical, photothermal, and facile surface chemical properties of gold and silver nanoparticles in biodiagnostics, therapy, and drug delivery. Archives of Toxicology, 88, 1391–1417.

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

39

Baptista, P.  V., McCusker, M.  P., Carvalho, A., Ferreira, D.  A., Mohan, N.  M., Martins, M., & Fernandes, A. R. (2018). Nano-strategies to fight multidrug resistant bacteria—“A Battle of the Titans”. Frontiers in Microbiology, 9, 1441. Baram-Pinto, D., Shukla, S., Gedanken, A., & Sarid, R. (2010). Inhibition of HSV-1 attachment, entry, and cell-to-cell spread by functionalized multivalent gold nanoparticles. Small, 6(9), 1044–1050. Behzad, F., Naghib, S.  M., Tabatabaei, S.  N., Zare, Y., & Rhee, K.  Y. (2021). An overview of the plant-mediated green synthesis of noble metal nanoparticles for antibacterial applications. Journal of Industrial and Engineering Chemistry, 94, 92–104. Belloni, J., Marignier, J. L., & Mostafavi, M. (2020). Mechanisms of metal nanoparticles nucleation and growth studied by radiolysis. Radiation Physics and Chemistry, 169, 107952. Berbec, S., Żołądek, S., Jabłońska, A., & Pałys, B. (2018). Electrochemically reduced graphene oxide on gold nanoparticles modified with a polyoxomolybdate film. Highly sensitive non-­ enzymatic electrochemical detection of H2O2. Sensors and Actuators B: Chemical, 258, 745–756. Bharadwaj, K. K., Rabha, B., Pati, S., Sarkar, T., Choudhury, B. K., Barman, A., et al. (2021). Green synthesis of gold nanoparticles using plant extracts as beneficial prospect for cancer theranostics. Molecules, 26(21), 6389. Biehler, E., Quach, Q., & Abdel-Fattah, T. M. (2023). Gold nanoparticles AuNP decorated on fused graphene-like materials for application in a hydrogen generation. Materials, 16(13), 4779. Bolanos, K., Kogan, M.  J., & Araya, E. (2019). Capping gold nanoparticles with albumin to improve their biomedical properties. International Journal of Nanomedicine, 14, 6387–6406. Brust, M., Walker, M., Bethell, D., Schiffrin, D.  J., & Whyman, R. (1994). Synthesis of thiol-­ derivatised gold nanoparticles in a two-phase liquid–liquid system. Journal of the Chemical Society, Chemical Communications., 7, 801–802. Budhadev, D., Poole, E., Nehlmeier, I., Liu, Y., Hooper, J., Kalverda, E., et al. (2020). Glycan-­ gold nanoparticles as multifunctional probes for multivalent lectin–carbohydrate binding: Implications for blocking virus infection and nanoparticle assembly. Journal of the American Chemical Society, 142(42), 18022–18034. Byrne, H. J., Lynch, I., De Jong, W. H., Kreyling, W. G., Loft, S., Park, M. V. D. Z., et al. (2010). Protocols for assessment of biological hazards of engineered nanomaterials. NanoImpactNet Reports. Cagno, V., Andreozzi, P., D’Alicarnasso, M., Jacob Silva, P., Mueller, M., Galloux, M., et  al. (2018). Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism. Nature Materials, 17(2), 195–203. Castro-Longoria, E., Vilchis-Nestor, A. R., & Avalos-Borja, M. (2011). Biosynthesis of silver, gold and bimetallic nanoparticles using the filamentous fungus Neurospora crassa. Colloids and Surfaces B: Biointerfaces, 83(1), 42–48. Chen, L., & Liang, J. (2020). An overview of functional nanoparticles as novel emerging antiviral therapeutic agents. Materials Science and Engineering: C, 112, 110924. Cherian, T., Maity, D., Rajendra Kumar, R.  T., Balasubramani, G., Ragavendran, C., Yalla, S., et  al. (2022). Green chemistry based gold nanoparticles synthesis using the marine bacterium Lysinibacillus odysseyi PBCW2 and their multitudinous activities. Nanomaterials, 12(17), 2940. Connor, E. E., Mwamuka, J., Gole, A., Murphy, C. J., & Wyatt, M. D. (2005). Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small, 1(3), 325–327. Cui, Y., Zhao, Y., Tian, Y., Zhang, W., Lü, X., & Jiang, X. (2012). The molecular mechanism of action of bactericidal gold nanoparticles on Escherichia coli. Biomaterials, 33(7), 2327–2333. De Crozals, G., Bonnet, R., Farre, C., & Chaix, C. (2016). Nanoparticles with multiple properties for biomedical applications: A strategic guide. Nano Today, 11(4), 435–463. Dey, G. R., El Omar, A. K., Jacob, J. A., Mostafavi, M., & Belloni, J. (2011). Mechanism of trivalent gold reduction and reactivity of transient divalent and monovalent gold ions studied by gamma and pulse radiolysis. The Journal of Physical Chemistry A, 115(4), 383–391.

40

M. Gnanaraj et al.

Dispenza, C., Spadaro, G., & Jonsson, M. (2017). Radiation engineering of multifunctional nanogels. In Applications of radiation chemistry in the fields of industry, biotechnology and environment (pp. 95–120). Do, P. Q. T., Huong, V. T., Phuong, N. T. T., Nguyen, T. H., Ta, H. K. T., Ju, H., et al. (2020). The highly sensitive determination of serotonin by using gold nanoparticles (Au NPs) with a localized surface plasmon resonance (LSPR) absorption wavelength in the visible region. RSC Advances, 10(51), 30858–30869. Doghish, A.  S., Hashem, A.  H., Shehabeldine, A.  M., Sallam, A.  A. M., El-Sayyad, G.  S., & Salem, S. S. (2022). Nanocomposite based on gold nanoparticles and carboxymethyl cellulose: Synthesis, characterization, antimicrobial, and anticancer activities. Journal of Drug Delivery Science and Technology, 77, 103874. Dreaden, E. C., Alkilany, A. M., Huang, X., Murphy, C. J., & El-Sayed, M. A. (2012). The golden age: Gold nanoparticles for biomedicine. Chemical Society Reviews, 41(7), 2740–2779. Du, B., Tian, L., Gu, X., Li, D., Wang, E., & Wang, J. (2015). Anionic lipid, pH-sensitive liposome-­ gold nanoparticle hybrids for gene delivery–quantitative research of the mechanism. Small, 11(19), 2333–2340. Duncan, T. V. (2011). Applications of nanotechnology in food packaging and food safety: Barrier materials, antimicrobials and sensors. Journal of Colloid and Interface Science, 363(1), 1–24. Edwards, P. P., & Thomas, J. M. (2007). Gold in a metallic divided state—From faraday to present-­ day nanoscience. Angewandte Chemie International Edition, 46(29), 5480–5486. Fan, J., Cheng, Y., & Sun, M. (2020). Functionalized gold nanoparticles: Synthesis, properties and biomedical applications. The Chemical Record, 20(12), 1474–1504. Farzin, L., Shamsipur, M., Samandari, L., & Sheibani, S. (2020). HIV biosensors for early diagnosis of infection: The intertwine of nanotechnology with sensing strategies. Talanta, 206, 120201. Fischer, H. C., & Chan, W. C. (2007). Nanotoxicity: The growing need for in vivo study. Current Opinion in Biotechnology, 18(6), 565–571. Ghaffari, E., Rezatofighi, S. E., Ardakani, M. R., & Rastegarzadeh, S. (2019). Delivery of antisense peptide nucleic acid by gold nanoparticles for the inhibition of virus replication. Nanomedicine, 14(14), 1827–1840. Ghosal, K. (2023). Tackling COVID-19 using antiviral nanocoating’s—Recent Progress and future challenges. Particle & Particle Systems Characterization, 40(1), 2200154. Giasuddin, A. S. M., Jhuma, K. A., & Haq, A. M. (2012). Use of gold nanoparticles in diagnostics, surgery and medicine: A review. Bangladesh Journal of Medical Biochemistry, 5(2), 56–60. Gou, X. X., Liu, T., Wang, Y. Y., & Han, Y. F. (2020). Ultrastable and highly catalytically active N-heterocyclic-Carbene-stabilized gold nanoparticles in confined spaces. Angewandte Chemie International Edition, 59(38), 16683–16689. Guglielmelli, A., Rosa, P., Contardi, M., Prato, M., Mangino, G., Miglietta, S., et  al. (2020). Biomimetic keratin gold nanoparticle-mediated in vitro photothermal therapy on glioblastoma multiforme. Nanomedicine, 16(2), 121–138. Gupta, N., & Malviya, R. (2021). Understanding and advancement in gold nanoparticle targeted photothermal therapy of cancer. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1875(2), 188532. Gupta, R., & Xie, H. (2018). Nanoparticles in daily life: Applications, toxicity and regulations. Journal of Environmental Pathology, Toxicology and Oncology, 37(3), 209. Gupta, A., Mumtaz, S., Li, C.  H., Hussain, I., & Rotello, V.  M. (2019). Combatting antibiotic-­ resistant bacteria using nanomaterials. Chemical Society Reviews, 48(2), 415–427. Hammami, I., & Alabdallah, N. M. (2021). Gold nanoparticles: Synthesis properties and applications. Journal of King Saud University-Science, 33(7), 101560. Hassan, H., Sharma, P., Hasan, M.  R., Singh, S., Thakur, D., & Narang, J. (2022). Gold nanomaterials–The golden approach from synthesis to applications. Materials Science for Energy Technologies, 5, 375. He, K., Jiang, Y., Wang, T., Liu, Z., Wang, M., Pan, L., & Chen, X. (2022). Assemblies and composites of gold nanostructures for functional devices: Nanoscience: Special Issue Dedicated to Professor Paul S. Weiss. Aggregate, 3(4), e57.

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

41

Herizchi, R., Abbasi, E., Milani, M., & Akbarzadeh, A. (2016). Current methods for synthesis of gold nanoparticles. Artificial Cells, Nanomedicine, and Biotechnology, 44(2), 596–602. Hernandez-Díaz, J.  A., Garza-García, J.  J., Zamudio-Ojeda, A., León-Morales, J.  M., López-­ Velázquez, J.  C., & García-Morales, S. (2021). Plant-mediated synthesis of nanoparticles and their antimicrobial activity against phytopathogens. Journal of the Science of Food and Agriculture, 101(4), 1270–1287. Hoshyar, N., Gray, S., Han, H., & Bao, G. (2016). The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine, 11(6), 673–692. Hosny, M., Fawzy, M., El-Badry, Y. A., Hussein, E. E., & Eltaweil, A. S. (2022a). Plant-assisted synthesis of gold nanoparticles for photocatalytic, anticancer, and antioxidant applications. Journal of Saudi Chemical Society, 26(2), 101419. Hosny, M., Eltaweil, A. S., Mostafa, M., El-Badry, Y. A., Hussein, E. E., Omer, A. M., & Fawzy, M. (2022b). Facile synthesis of gold nanoparticles for anticancer, antioxidant applications, and photocatalytic degradation of toxic organic pollutants. ACS Omega, 7(3), 3121–3133. Hryniewicz, B. M., Volpe, J., Bach-Toledo, L., Kurpel, K. C., Deller, A. E., Soares, A. L., et al. (2022). Development of polypyrrole (nano) structures decorated with gold nanoparticles toward immunosensing for COVID-19 serological diagnosis. Materials Today Chemistry, 24, 100817. Hu, M., Chen, J., Li, Z.  Y., Au, L., Hartland, G.  V., Li, X., et  al. (2006). Gold nanostructures: Engineering their plasmonic properties for biomedical applications. Chemical Society Reviews, 35(11), 1084–1094. Huang, C.  J., Chiu, P.  H., Wang, Y.  H., Chen, K.  L., Linn, J.  J., & Yang, C.  F. (2006). Electrochemically controlling the size of gold nanoparticles. Journal of the Electrochemical Society, 153(12), D193. Huang, X., Jain, P. K., El-Sayed, I. H., & El-Sayed, M. A. (2007). Gold nanoparticles: Interesting optical properties and recent applications in cancer diagnostics and therapy. Nanomedicine (London, England), 2(5), 681–693. Huang, H., Zhao, J., Weng, B., Lai, F., Zhang, M., Hofkens, J., et al. (2022). Site-sensitive selective CO2 Photoreduction to CO over gold nanoparticles. Angewandte Chemie International Edition, 61(28), e202204563. Jennings, T., & Strouse, G. (2007). Past, present, and future of gold nanoparticles. Bio-Applications of Nanoparticles, 620, 34–47. Jeong, E.  H., Jung, G., Hong, C.  A., & Lee, H. (2014). Gold nanoparticle (AuNP)-based drug delivery and molecular imaging for biomedical applications. Archives of Pharmacal Research, 37, 53–59. Kamaraj, C., Karthi, S., Reegan, A. D., Balasubramani, G., Ramkumar, G., Kalaivani, K., et al. (2022). Green synthesis of gold nanoparticles using Gracilaria crassa leaf extract and their ecotoxicological potential: Issues to be considered. Environmental Research, 213, 113711. Kannan, R., Rahing, V., Cutler, C., Pandrapragada, R., Katti, K. K., Kattumuri, V., et al. (2006). Nanocompatible chemistry toward fabrication of target-specific gold nanoparticles. Journal of the American Chemical Society, 128(35), 11342–11343. Karthikeyan, C., Sisubalan, N., Sridevi, M., Varaprasad, K., Basha, M.  H. G., Shucai, W., & Sadiku, R. (2021). Biocidal chitosan-magnesium oxide nanoparticles via a green precipitation process. Journal of Hazardous Materials, 411, 124884. Khan, A. U., Yuan, Q., Wei, Y., Khan, G. M., Khan, Z. U. H., Khan, S., et al. (2016). Photocatalytic and antibacterial response of biosynthesized gold nanoparticles. Journal of Photochemistry and Photobiology B: Biology, 162, 273–277. Khan, Y., Sadia, H., Ali Shah, S.  Z., Khan, M.  N., Shah, A.  A., Ullah, N., et  al. (2022). Classification, synthetic, and characterization approaches to nanoparticles, and their applications in various fields of nanotechnology: A review. Catalysts, 12(11), 1386. Kumar, V.  G., Gokavarapu, S.  D., Rajeswari, A., Dhas, T.  S., Karthick, V., Kapadia, Z., et  al. (2011). Facile green synthesis of gold nanoparticles using leaf extract of antidiabetic potent Cassia auriculata. Colloids and Surfaces B: Biointerfaces, 87(1), 159–163. Kumar, V., Patil, V., Apte, A., Harale, N., Patil, P., & Kulkarni, S. (2015). Ultrasensitive gold nanostar–polyaniline composite for ammonia gas sensing. Langmuir, 31(48), 13247–13256.

42

M. Gnanaraj et al.

Lee, H., & Lee, D. G. (2018). Gold nanoparticles induce a reactive oxygen species-independent apoptotic pathway in Escherichia coli. Colloids and Surfaces B: Biointerfaces, 167, 1–7. Lee, J. H., Cho, H. Y., Choi, H. K., Lee, J. Y., & Choi, J. W. (2018). Application of gold nanoparticle to plasmonic biosensors. International Journal of Molecular Sciences, 19(7), 2021. Lim, Z. Z. J., Li, J. E. J., Ng, C. T., Yung, L. Y. L., & Bay, B. H. (2011). Gold nanoparticles in cancer therapy. Acta Pharmacologica Sinica, 32(8), 983–990. Lin, N., Verma, D., Saini, N., Arbi, R., Munir, M., Jovic, M., & Turak, A. (2021). Antiviral nanoparticles for sanitizing surfaces: A roadmap to self-sterilizing against COVID-19. Nano Today, 40, 101267. Liu, Z., Persson, S., & Sánchez-Rodríguez, C. (2015). At the border: The plasma membrane–cell wall continuum. Journal of Experimental Botany, 66(6), 1553–1563. Liu, J., Wang, N., & Ma, L. (2020a). Recent advances in covalent organic frameworks for catalysis. Chemistry–An Asian Journal, 15(3), 338–351. Liu, X., Zhang, Q., Knoll, W., Liedberg, B., & Wang, Y. (2020b). Rational design of functional peptide–gold hybrid nanomaterials for molecular interactions. Advanced Materials, 32(37), 2000866. Mahalingam, S., Xu, Z., & Edirisinghe, M. (2015). Antibacterial activity and biosensing of PVA-­ lysozyme microbubbles formed by pressurized gyration. Langmuir, 31(36), 9771–9780. Marinoiu, A., Raceanu, M., Andrulevicius, M., Tamuleviciene, A., Tamulevicius, T., Nica, S., et al. (2020). Low-cost preparation method of well dispersed gold nanoparticles on reduced graphene oxide and electrocatalytic stability in PEM fuel cell. Arabian Journal of Chemistry, 13(1), 3585–3600. Marsden, J., & House, I. (2006). The chemistry of gold extraction. SME. Medhi, R., Srinoi, P., Ngo, N., Tran, H. V., & Lee, T. R. (2020). Nanoparticle-based strategies to combat COVID-19. ACS Applied Nano Materials, 3(9), 8557–8580. Melendez-Villanueva, M. A., Morán-Santibañez, K., Martínez-Sanmiguel, J. J., Rangel-López, R., Garza-Navarro, M. A., Rodríguez-Padilla, C., et al. (2019). Virucidal activity of gold nanoparticles synthesized by green chemistry using garlic extract. Viruses, 11(12), 1111. Mieszawska, A. J., Mulder, W. J., Fayad, Z. A., & Cormode, D. P. (2013). Multifunctional gold nanoparticles for diagnosis and therapy of disease. Molecular Pharmaceutics, 10(3), 831–847. Mikhailova, E. O. (2021). Gold nanoparticles: Biosynthesis and potential of biomedical application. Journal of Functional Biomaterials, 12(4), 70. Monroe, M.  K., Wang, H., Anderson, C.  F., Jia, H., Flexner, C., & Cui, H. (2022). Leveraging the therapeutic, biological, and self-assembling potential of peptides for the treatment of viral infections. Journal of Controlled Release, 348, 1028–1049. Mortezaee, K., Najafi, M., Samadian, H., Barabadi, H., Azarnezhad, A., & Ahmadi, A. (2019). Redox interactions and genotoxicity of metal-based nanoparticles: A comprehensive review. Chemico-Biological Interactions, 312, 108814. Murthy, S. K. (2007). Nanoparticles in modern medicine: State of the art and future challenges. International Journal of Nanomedicine, 2(2), 129–141. Naveena, B.  E., & Prakash, S. (2013). Biological synthesis of gold nanoparticles using marine algae Gracilaria corticata and its application as a potent antimicrobial and antioxidant agent. Asian Journal of Pharmaceutical and Clinical Research, 6(2), 179–182. Nishanthi, R., Malathi, S., & Palani, P. (2019). Green synthesis and characterization of bioinspired silver, gold and platinum nanoparticles and evaluation of their synergistic antibacterial activity after combining with different classes of antibiotics. Materials Science and Engineering: C, 96, 693–707. Nosrati, H., Seidi, F., Hosseinmirzaei, A., Mousazadeh, N., Mohammadi, A., Ghaffarlou, M., et al. (2022). Prodrug polymeric nanoconjugates encapsulating gold nanoparticles for enhanced X-Ray radiation therapy in breast cancer. Advanced Healthcare Materials, 11(3), 2102321. Oza, G., Pandey, S., Mewada, A., Kalita, G., Sharon, M., Phata, J., et al. (2012). Facile biosynthesis of gold nanoparticles exploiting optimum pH and temperature of fresh water algae Chlorella pyrenoidusa. Advances in Applied Science Research, 3(3), 1405–1412.

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

43

Paradowska, E., Studzińska, M., Jabłońska, A., Lozovski, V., Rusinchuk, N., Mukha, I., et  al. (2021). Antiviral effect of nonfunctionalized gold nanoparticles against herpes simplex virus type-1 (HSV-1) and possible contribution of near-field interaction mechanism. Molecules, 26(19), 5960. Paramasivam, G., Kayambu, N., Rabel, A. M., Sundramoorthy, A. K., & Sundaramurthy, A. (2017). Anisotropic noble metal nanoparticles: Synthesis, surface functionalization and applications in biosensing, bioimaging, drug delivery and theranostics. Acta Biomaterialia, 49, 45–65. Parthiban, A., Sachithanandam, V., Sarangapany, S., Misra, R., Muthukrishnan, P., Jeyakumar, T. C., et al. (2023). Green synthesis of gold nanoparticles using quercetin biomolecule from mangrove plant, Ceriops tagal: Assessment of antiproliferative properties, cellular uptake and DFT studies. Journal of Molecular Structure, 1272, 134167. Patil, T. P., Vibhute, A. A., Patil, S. L., Dongale, T. D., & Tiwari, A. P. (2023). Green synthesis of gold nanoparticles via Capsicum annum fruit extract: Characterization, antiangiogenic, antioxidant and anti-inflammatory activities. Applied Surface Science Advances, 13, 100372. Pearce, A. K., Wilks, T. R., Arno, M. C., & O’Reilly, R. K. (2021). Synthesis and applications of anisotropic nanoparticles with precisely defined dimensions. Nature Reviews Chemistry, 5(1), 21–45. Pelgrift, R. Y., & Friedman, A. J. (2013). Nanotechnology as a therapeutic tool to combat microbial resistance. Advanced Drug Delivery Reviews, 65(13–14), 1803–1815. Pourali, P., Badiee, S. H., Manafi, S., Noorani, T., Rezaei, A., & Yahyaei, B. (2017). Biosynthesis of gold nanoparticles by two bacterial and fungal strains, Bacillus cereus and Fusarium oxysporum, and assessment and comparison of their nanotoxicity in vitro by direct and indirect assays. Electronic Journal of Biotechnology, 29, 86–93. Pradeep, T. (2009). Noble metal nanoparticles for water purification: A critical review. Thin Solid Films, 517(24), 6441–6478. Rafiei, S., Rezatofighi, S. E., Ardakani, M. R., & Rastegarzadeh, S. (2015). Gold nanoparticles impair foot-and-mouth disease virus replication. IEEE Transactions on Nanobioscience, 15(1), 34–40. Rajan, A., Vilas, V., & Philip, D. (2015). Studies on catalytic, antioxidant, antibacterial and anticancer activities of biogenic gold nanoparticles. Journal of Molecular Liquids, 212, 331–339. Reina, G., Peng, S., Jacquemin, L., Andrade, A. F., & Bianco, A. (2020). Hard nanomaterials in time of viral pandemics. ACS Nano, 14(8), 9364–9388. Rickard, D. (2015). Pyrite: A natural history of fool’s gold. Oxford University Press. Rosli, N. A., Teow, Y. H., & Mahmoudi, E. (2021). Current approaches for the exploration of antimicrobial activities of nanoparticles. Science and Technology of Advanced Materials, 22(1), 885–907. Rowe, L. A., Degtyareva, N., & Doetsch, P. W. (2008). DNA damage-induced reactive oxygen species (ROS) stress response in Saccharomyces cerevisiae. Free Radical Biology and Medicine, 45(8), 1167–1177. Sani, A., Cao, C., & Cui, D. (2021). Toxicity of gold nanoparticles (AuNPs): A review. Biochemistry and Biophysics Reports, 26, 100991. Shah, M., Badwaik, V., Kherde, Y., Waghwani, H.  K., Modi, T., Aguilar, Z.  P., et  al. (2014). Gold nanoparticles: Various methods of synthesis and antibacterial applications. Frontiers in Bioscience, 19(8), 1320. Sharma, N., Pinnaka, A. K., Raje, M., Fnu, A., Bhattacharyya, M. S., & Choudhury, A. R. (2012). Exploitation of marine bacteria for production of gold nanoparticles. Microbial Cell Factories, 11, 1–6. Sharma, B., Purkayastha, D. D., Hazra, S., Gogoi, L., Bhattacharjee, C. R., Ghosh, N. N., & Rout, J. (2014a). Biosynthesis of gold nanoparticles using a freshwater green alga, Prasiola crispa. Materials Letters, 116, 94–97. Sharma, B., Purkayastha, D. D., Hazra, S., Thajamanbi, M., Bhattacharjee, C. R., Ghosh, N. N., & Rout, J. (2014b). Biosynthesis of fluorescent gold nanoparticles using an edible freshwater red alga, Lemanea fluviatilis (L.) C. Ag. and antioxidant activity of biomatrix loaded nanoparticles. Bioprocess and Biosystems Engineering, 37, 2559–2565.

44

M. Gnanaraj et al.

Sharmin, S., Rahaman, M. M., Sarkar, C., Atolani, O., Islam, M. T., & Adeyemi, O. S. (2021). Nanoparticles as antimicrobial and antiviral agents: A literature-based perspective study. Heliyon, 7(3), e06456. Sibuyi, N.  R. S., Moabelo, K.  L., Fadaka, A.  O., Meyer, S., Onani, M.  O., Madiehe, A.  M., & Meyer, M. (2021). Multifunctional gold nanoparticles for improved diagnostic and therapeutic applications: A review. Nanoscale Research Letters, 16, 1–27. Singh, P. K., & Kundu, S. (2014). Biosynthesis of gold nanoparticles using bacteria. Proceedings of the National Academy of Sciences, India Section B: Biological Sciences, 84, 331–336. Singh, N., Manshian, B., Jenkins, G.  J., Griffiths, S.  M., Williams, P.  M., Maffeis, T.  G., et  al. (2009). NanoGenotoxicology: The DNA damaging potential of engineered nanomaterials. Biomaterials, 30(23–24), 3891–3914. Singh, P., Pandit, S., Mokkapati, V.  R. S.  S., Garg, A., Ravikumar, V., & Mijakovic, I. (2018). Gold nanoparticles in diagnostics and therapeutics for human cancer. International Journal of Molecular Sciences, 19(7), 1979. Sisubalan, N., Ramkumar, V.  S., Pugazhendhi, A., Karthikeyan, C., Indira, K., Gopinath, K., Hameed, A. S., & Basha, M. H. (2018). ROS-mediated cytotoxic activity of ZnO and CeO2 nanoparticles synthesized using the Rubia cordifolia L. leaf extract on MG-63 human osteosarcoma cell lines. Environmental Science and Pollution Research, 25, 10482–10492. Siti, R. M., Khairunisak, A. R., Aziz, A. A., & Noordin, R. (2013). Green synthesis of 10 nm gold nanoparticles via seeded-growth method and its conjugation properties on lateral flow immunoassay. Advanced Materials Research, 686, 8–12. Sivakami, A., Sarankumar, R., & Vinodha, S. (2021). Introduction to nanobiotechnology: Novel and smart applications (pp. 1–22). Perspectives and Promotion. Skladanowski, M., Wypij, M., Laskowski, D., Golińska, P., Dahm, H., & Rai, M. (2017). Silver and gold nanoparticles synthesized from Streptomyces sp. isolated from acid forest soil with special reference to its antibacterial activity against pathogens. Journal of Cluster Science, 28, 59–79. Soltani Nejad, M., Samandari Najafabadi, N., Aghighi, S., Pakina, E., & Zargar, M. (2022). Evaluation of Phoma sp. biomass as an endophytic fungus for synthesis of extracellular gold nanoparticles with antibacterial and antifungal properties. Molecules, 27(4), 1181. Song, J., Huang, P., Duan, H., & Chen, X. (2015). Plasmonic vesicles of amphiphilic nanocrystals: Optically active multifunctional platform for cancer diagnosis and therapy. Accounts of Chemical Research, 48(9), 2506–2515. Sperling, R. A., & Parak, W. J. (2010). Surface modification, functionalization and bioconjugation of colloidal inorganic nanoparticles. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 368(1915), 1333–1383. Steinmetz, N. F., & Manchester, M. (2011). Viral nanoparticles: Tools for material science and biomedicine. Pan Stanford Publishing. Subbulakshmi, A., Durgadevi, S., Anitha, S., Govarthanan, M., Biruntha, M., Rameshthangam, P., & Kumar, P. (2023). Biogenic gold nanoparticles from Gelidiella acerosa: Bactericidal and photocatalytic degradation of two commercial dyes. Applied Nanoscience, 13(6), 4033–4042. Suganya, K.  U., Govindaraju, K., Kumar, V.  G., Dhas, T.  S., Karthick, V., Singaravelu, G., & Elanchezhiyan, M. (2015). Blue green alga mediated synthesis of gold nanoparticles and its antibacterial efficacy against Gram positive organisms. Materials Science and Engineering: C, 47, 351–356. Sulaiman, G. M., Waheeb, H. M., Jabir, M. S., Khazaal, S. H., Dewir, Y. H., & Naidoo, Y. (2020). Hesperidin loaded on gold nanoparticles as a drug delivery system for a successful biocompatible, anti-cancer, anti-inflammatory and phagocytosis inducer model. Scientific Reports, 10(1), 9362. Sun, Y., & Xia, Y. (2002). Shape-controlled synthesis of gold and silver nanoparticles. Science, 298(5601), 2176–2179. Suriyakala, G., Sathiyaraj, S., Babujanarthanam, R., Alarjani, K.  M., Hussein, D.  S., Rasheed, R.  A., & Kanimozhi, K. (2022). Green synthesis of gold nanoparticles using Jatropha integerrima Jacq. flower extract and their antibacterial activity. Journal of King Saud University-­ Science, 34(3), 101830.

Gold Nanoparticles as Antibacterial and Antiviral Agents: Biomedical Applications…

45

Tatur, S., Maccarini, M., Barker, R., Nelson, A., & Fragneto, G. (2013). Effect of functionalized gold nanoparticles on floating lipid bilayers. Langmuir, 29(22), 6606–6614. Thakur, S., Thakur, S., & Kumar, R. (2018). Bio-nanotechnology and its role in agriculture and food industry. Journal of Molecular and Genetic Medicine, 12(324), 1747–0862. Thompson, C. I., Barclay, W. S., & Zambon, M. C. (2004). Changes in in vitro susceptibility of influenza A H3N2 viruses to a neuraminidase inhibitor drug during evolution in the human host. Journal of Antimicrobial Chemotherapy, 53(5), 759–765. Tonelli, F. M. P., Silva, C. S., Delgado, V. M. S., & Tonelli, F. C. P. (2023). Algae-based green AgNPs, AuNPs, and FeNPs as potential nanoremediators. Green Processing and Synthesis, 12(1), 20230008. Turkevich, J., Stevenson, P. C., & Hillier, J. (1951). A study of the nucleation and growth processes in the synthesis of colloidal gold. Discussions of the Faraday Society, 11, 55–75. Uboldi, C., Bonacchi, D., Lorenzi, G., Hermanns, M., Pohl, C., Baldi, G., et  al. (2009). Gold nanoparticles induce cytotoxicity in the alveolar type-II cell lines A549 and NCIH441. Particle and Fibre Toxicology, 6(1), 1–12. Van Doren, E. A., De Temmerman, P. J. R., Francisco, M. A. D., & Mast, J. (2011). Determination of the volume-specific surface area by using transmission electron tomography for characterization and definition of nanomaterials. Journal of Nanobiotechnology, 9(1), 1–8. Vodyashkin, A.  A., Rizk, M.  G. H., Kezimana, P., Kirichuk, A.  A., & Stanishevskiy, Y. M. (2021). Application of gold nanoparticle-based materials in cancer therapy and diagnostics. ChemEngineering, 5(4), 69. Vonnemann, J., Sieben, C., Wolff, C., Ludwig, K., Böttcher, C., Herrmann, A., & Haag, R. (2014). Virus inhibition induced by polyvalent nanoparticles of different sizes. Nanoscale, 6(4), 2353–2360. Waheed, S., Li, Z., Zhang, F., Chiarini, A., Armato, U., & Wu, J. (2022). Engineering nano-­ drug biointerface to overcome biological barriers toward precision drug delivery. Journal of Nanobiotechnology, 20(1), 395. Yah, C. S. (2013). The toxicity of gold nanoparticles in relation to their physiochemical properties. Biomedical Research, 24(3), 400–413. Yang, W., Liang, H., Ma, S., Wang, D., & Huang, J. (2019). Gold nanoparticle based photothermal therapy: Development and application for effective cancer treatment. Sustainable Materials and Technologies, 22, e00109. Yasamineh, S., Kalajahi, H. G., Yasamineh, P., Yazdani, Y., Gholizadeh, O., Tabatabaie, R., et al. (2022). An overview on nanoparticle-based strategies to fight viral infections with a focus on COVID-19. Journal of Nanobiotechnology, 20(1), 1–26. Ye, J., Zhu, B., Cheng, B., Jiang, C., Wageh, S., Al-Ghamdi, A.  A., & Yu, J. (2022). Synergy between platinum and gold nanoparticles in oxygen activation for enhanced room-temperature formaldehyde oxidation. Advanced Functional Materials, 32(15), 2110423. Zhang, L., Gu, F.  X., Chan, J.  M., Wang, A.  Z., Langer, R.  S., & Farokhzad, O.  C. (2008). Nanoparticles in medicine: Therapeutic applications and developments. Clinical Pharmacology & Therapeutics, 83(5), 761–769. Zhang, X.  D., Wu, D., Shen, X., Liu, P.  X., Yang, N., Zhao, B., et  al. (2011). Size-dependent in vivo toxicity of PEG-coated gold nanoparticles. International Journal of Nanomedicine, 6, 2071–2081.

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral Perspectives S. Shiva Samhitha, Srivathsava Surabhi, Sai Keerthi Saireddy, and G. Santhosh

Overviews Nanotechnology is a fast-growing field with extensive applications in biomedical engineering and nanomedicine. Nanoparticles exhibit distinctive physicochemical and optoelectronic characteristics, rendering them extremely attractive for a variety of potential applications. These applications encompass chemical sensing, electronic device fabrication, catalysis, pharmaceutical development, antimicrobial efficacy, as well as medical diagnostics and imaging (Mohanraj & Chen, 2006; Jan

S. S. Samhitha (*) Research Group in Advanced Nanocomposites (GINA), Department of Materials Engineering (DIMAT), Faculty of Engineering, University of Concepción, Concepción, Chile e-mail: [email protected] S. Surabhi Research Group in Advanced Nanocomposites (GINA), Department of Materials Engineering (DIMAT), Faculty of Engineering, University of Concepción, Concepción, Chile Nanosciences and Nanotechnology Laboratory, Faculty of Mathematical Physical Sciences (FCFM), Universidad Autónoma de Nuevo León (UANL), San Nicolás de los Garza, Nuevo León, Mexico S. K. Saireddy Department of General Medicine, Chalmeda Anand Rao Institute of Medical Sciences, Karimnagar, Telangana, India G. Santhosh Nano-Materials and Energy Devices Lab (NMEDL), Department of Mechanical Engineering, NMAM Institute of Technology, Nitte (Deemed to be University), Deralakatte, Karnataka, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_3

47

48

S. S. Samhitha et al.

et al., 2020). The utilization of bio-compatible nanoparticles in the healthcare sector is predominantly focused on their applications in the areas of diagnosis, treatment, drug delivery, and formulation of novel medicines (Kubik et al., 2016; Smith et al., 2013). Platinum nanoparticles (PtNPs) have gained significant attention in various fields, including medical, biological, electrical, and chemical applications, owing to their exceptional biocompatibility, stability, and surface chemistry (Johnstone et al., 2016). PtNPs exhibit remarkable cellular biocompatibility, equivalent to that of gold nanoparticles (Shiny et  al., 2014). However, they possess an increased cytotoxic impact (Hashimoto et al., 2016). This characteristic renders them potentially valuable in the realm of cancer therapy, as platinum ions can engage with DNA and impede its replication (Mohammadi et al., 2013). PtNPs also exhibit antibacterial properties against both Gram-positive and Gram-negative pathogens, similar to silver nanoparticles (AgNPs); however, AgNPs possess a higher level of toxicity compared to toxicity level than PtNPs, thereby imposing constraints on their potential clinical applications (Nishanthi et al., 2019). The applications of PtNPs are determined by their shape, size, dispersion, and morphology (Gangula et al., 2011). For example, cubic PtNPs have been observed to function as a catalyst in the process of adsorption and oxidation of carbon monoxide (CO) (Kweskin et al., 2006). PtNPs have demonstrated significant utility as catalysts in proton exchange membrane fuel cells (Schmidt et al., 1999). Additionally, they have found widespread application in various hydrogenation processes, such as o-chloronitrobenzene and cinnamaldehyde hydrogenation (Cheng et  al., 2009). Various conventional methods have been employed for the preparation of PtNPs, including UV chemical reduction, electrolysis method, laser ablation, vapor deposition, thermal decomposition, irradiation reduction, ion implantation, sol–gel route, chemical precipitation, and micro-wave processing techniques (Tahir et al., 2017; Zheng et al., 2013; Ke et al., 2013; Paschos et al., 2008).

Advantages and Disadvantages of PtNPs Advantages Catalytic Activity Among the group of noble metals, platinum (Pt) stands out due to its notable characteristics, including a significantly high melting point of 1769 °C, which contributes to its resistance against chemical attacks and corrosion. This particular metal demonstrates high catalytic efficiency in many catalytic reactions, such as hydrogenation reactions (Williams & Burstein, 1997). The optimization of catalytic activities associated with platinum (Pt) can be achieved through the utilization of protective agents, such as dendrimers, PVP (polyvinylpyrrolidone), triblock copolymers, and other similar compounds. These agents facilitate the formation of

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral…

49

nanoparticles, which in turn enhance the catalytic performance of Pt (Niesz et al., 2005; Teranishi et al., 1999). Electrical Conductivity Platinum, as a noble metal, has notable electrical conductivity in its bulk state, and this characteristic persists even at the nanoscale level. The metallic behavior exhibited by metals can be attributed to the existence of unbound electrons inside their electronic configuration, which possess a high degree of mobility and can readily respond to an applied electric field. Biocompatibility Platinum exhibits a notable degree of biocompatibility, rendering PtNPs well suited for several medical applications, including drug delivery, imaging, and therapeutic agents (Abed et al., 2022). However, its biocompatibility depends on its purity and surface characteristics and the specific application it uses. Durability Platinum is renowned for its inherent capacity to resist corrosion and oxidation, hence guaranteeing the stability and durability of PtNPs across diverse environmental conditions.

Disadvantages Cost Platinum, classified as a precious metal, exhibits a notable drawback in the form of its considerable cost, which can pose a significant impediment to its extensive applications. This cost disadvantage becomes particularly apparent when comparing platinum to alternative catalysts or materials that are comparatively more affordable. Toxicity Although platinum is widely acknowledged as being biocompatible, there may be concerns regarding potential toxicity in specific situations due to the small size and enhanced reactivity of PtNPs. Further investigation is required in order to comprehensively comprehend the safety characteristics of PtNPs (Jan et al., 2021).

50

S. S. Samhitha et al.

Synthesis Challenges The synthesis of PtNPs that exhibit precise control over their size and shape poses a significant challenge. The attainment of consistent and scalable synthesis processes is necessary in order to facilitate their widespread application (Jeyaraj et al., 2019). Agglomeration Nanoparticles have a tendency to form agglomerates, a phenomenon that can significantly impact their properties and impede their intended applications. Effective stabilization and dispersion techniques are necessary in order to mitigate the occurrence of agglomeration. Environmental Impact The extraction and refinement of platinum possess significant environmental ramifications. The growing utilization of PtNPs across diverse sectors may have implications for the demand for Pt, potentially resulting in heightened mining activities and associated environmental considerations.

Antimicrobial and Antiviral Characteristics Antimicrobial Characteristics of PtNPs The widespread utilization of antibiotics to manage infectious diseases, has resulted in the emergence of a considerable multitude of pathogenic strains that exhibit resistance to antibiotics, thereby giving rise to significant challenges within the field of medicine. Due to the prevailing escalation in bacterial resistance, there is an urgent need for alternative agents that possess the ability to effectively combat pathogenic microorganisms while ensuring minimal toxicity to humans. The effects of nanoparticles on bacterial cells encompass various mechanisms, such as the disruption of the microbial cell wall and cell membrane, impairment of pump mechanisms, degradation of cellular components including ribosomes, inhibition of DNA replication, dysfunction of enzymes, the process of generating reactive oxygen species (ROS) can result in oxidative stress, stimulation of both innate and acquired immune responses, and prevention of biofilm formation (Salem & Fouda, 2021). The antibacterial efficacy is reliant upon the morphology, size, and shape of NPs, as well as their surface charges. Several metallic nanoparticles, including silver (Ag), platinum (Pt), gold (Au), palladium (Pd), zinc oxide (ZnO), and copper (Cu), have a negative zeta potential, which indicates their ability to cause damage to cells.

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral…

51

Despite the fact that PtNPs have a greater negative zeta potential and induce significant cellular damage, they demonstrate enhanced antibacterial efficacy (Chwalibog et al., 2010). Recent research highlighted the importance of PtNPs in human health and their use against microbe-induced diseases. In their study, Tahir et al. (2017) employed a green synthesis approach utilizing the aqueous extract derived from Taraxacum laevigatum; chosen due to its rich composition of various phenolic compounds, which played a crucial role in both the reduction and stabilization of PtNPs. The characterization results, indicate that the surfaces of the nanoparticles were coated with proteins, flavonoids, saponins, and polyphenols derived from the biosynthetic extract. The antimicrobial activity assessment showed inhibitory effects of the nanoparticles against Gram-positive bacteria, resulting in an average inhibition zone diameter of 18 mm with a standard deviation of ±0.8  mm and also against Gram-negative bacteria, with an average inhibition zone diameter of 15 mm and a standard deviation of ±0.5 mm. Nanoparticles’ antimicrobial properties are often attributed to their small size, typically around 5 nm, and their spherical shape. Similarly, Subramaniyan et al., (2018) synthesized effectively, PtNPs that were functionalized by phytoproteins derived from spinach leaves. In light of documented cases of foodborne illness caused by Salmonella typhi, an investigation was conducted to assess the antibacterial properties of this pathogenic bacterium where the minimal inhibitory concentration (MIC) was determined to be 12 μM. The susceptibility test resulted in the achievement of a 13-mm inhibitory halo. In the context of an in vivo experimental model, zebrafish were subjected to exposure to Salmonella typhi, a pathogenic bacterium. Following the infection, the zebrafish were subsequently administered functionalized nanoparticles via injection. The utilization of functionalized PtNPs in conjunction with phytoproteins exhibits considerable potential as a viable solution for addressing the prevalence of infectious diseases induced by Salmonella typhi. Ramkumar et al. (2017) employed an aqueous extract derived from the brown seaweed Padina gymnospora as a means to investigate the efficacy of PtNPs, both with and without PVP coatings, against various pathogens, including Escherichia coli (E. coli), Klebsiella, and other relevant microorganisms. The inhibitory zone of other strains was observed to measure between 13 and 14 millimeters. The extract derived from Padina gymnospora exhibited potential inhibitory effects on bacterial growth when applied to nanoparticles without the presence of PVP coating forming a zone of inhibition measuring between 2 and 3 mm. Lately, in their study, Ayaz Ahmed et al., (2016) investigated the antibacterial properties of PtNPs with a size range of 2–5  nm, which exhibited significant antibacterial activity against both Gram-positive and Gram-negative bacteria. The findings of this study indicate that the PtNPs exerted a significant impact on bacterial cell viability by inducing the production of ROS, thereby compromising the integrity of the bacterial cell membrane. Additionally, it was observed that the PtNPs contributed to an increased survival rate among zebrafish that were infected with the bacteria. The eco-friendly synthesis of PtNPs was reported by Jeyapaul et al., by utilizing leaf extracts derived from Jatropa gossypifolia and Jatropa glandulifera, as

52

S. S. Samhitha et al.

cost-effective reducing and capping agents for the synthesis of environmentally friendly PtNPs. The biologically synthesized PtNPs derived from leaf extracts have demonstrated significant potential in exhibiting medicinal drug activity against pathogenic bacteria and high antibacterial properties against Gram-positive and Gram-negative pathogenic bacteria (Nishanthi et al., 2019). PtNPs were synthesized utilizing date extracts derived from the Ajwa and Barni varieties. These PtNPs were subsequently subjected to testing against two bacterial strains, namely, E. coli and Bacillus subtilis. The Gram-negative bacteria yielded promising results, as reported in a study (Al-Radadi, 2019). Riyaz et al., synthesized PtNPs using Cinnamomum camphora leaf extract, which demonstrated significant antibacterial efficacy toward pathogenic bacteria (Bashir Wani et  al., 2023). Jenan et  al., (Taha et  al., 2023) employed a green synthesis method for PtNPs by the utilization of the fig extract of Ficus carica as a reducing agent. PtNPs were examined for their potential as antifungal and antibacterial agents such as Candida and Aspergillus, as well as Gram-­ positive Staphylococcus aureus (S. aureus) and Gram-negative Acinetobacter. The highest zone of inhibition was found to be 36 mm in the case of Candida spp. as compared to the 28 mm inhibition zone against Gram-positive S. aureus. The functionalization of silk with in situ synthesized PtNPs was reported by Zou et al., (2018) followed by subsequent in situ synthesis of PtNPs on silk fabrics via heat treatment; it was unequivocally ascertained that the application of PtNPs onto the silk materials resulted in the acquisition of various functionalities, including coloration, catalytic properties, and bactericidal activity, and a remarkable antibacterial effect against E. coli.

Antiviral and Antifungal Characteristics of PtNPs Chloroquine (CQ) and hydroxychloroquine (HCQ) have long been utilized as pharmacotherapies for the treatment of malaria. The preclinical investigations have provided evidence of the prophylactic and antiviral properties exhibited by CQ and HCQ against COVID-19 (Liu et al., 2020). The comparative clinical safety profile of HCQ is more favorable than that of CQ, thereby enabling its potential for prolonged use and higher daily dose. Morad et al., (2021) conducted simulation studies to illustrate the adsorption properties of HCQ and CQ on silver (Ag), gold (Au), silver–gold alloy (AgAu), and Pt nanoparticles. PtNPs exhibited the highest adsorption energy, followed by Au, AuAg, and Ag nanoparticles with decreasing adsorption energies. The results indicate that PtNP exhibits the highest affinity when compared to other nanoparticles due to the shorter distance between the O-group with PtNP, indicating the superior adsorption properties and explaining the greater affinity of PtNP to HCQ compared to CQ. López-Goerne et al., (2022) studied the antiviral properties of Pt/TiO2-SiO2 bionanocatalysts against influenza A (H1N1) virus in a post-infection model. The nanoparticles’ mechanism of action, which relies on RNA interaction, distinguishes them from conventional vaccinations that mostly interact with surface proteins. This unique characteristic enables the

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral…

53

nanoparticles to catalyze bond breaking, regardless of the arrangement of nucleotides. Theoretical studies propose that bionanocatalysts possess the potential to offer alternative pathways for the eradication of viruses. The bionanocatalysts composed of Pt/TiO2-SiO2 exhibit notable effectiveness in suppressing viral proliferation, specifically reducing it by 65.2% in the case of the influenza A (H1N1) virus strain. Moreover, by raising the concentration of the nanoparticles, and altering the nanoparticle/virus ratio, the efficacy can be further enhanced to achieve complete inhibition of viral proliferation, reaching up to 100%. The antifungal agents currently available in the market have been found to induce a range of adverse reactions, such as gastrointestinal disturbances manifesting as diarrhea, pyrexia or elevated body temperature, renal impairment leading to potential failure, and vestibular dysfunction resulting in vertigo. In the current context, it is essential to explore alternative treatment options for fungal diseases (Jan et al., 2020). The study conducted by Planivel et al. (Velmurugan et al., 2016) investigated the green synthesis of platinum nanoparticles utilizing an extract derived from the Prunus × yedoensis tree gum aimed to investigate the in-vitro antifungal activity of synthesized PtNPs in combination with a commercially available antifungal agent, investigating the efficacy of PtNPs, as well as a combination of extract and NPs, against two plant pathogenic fungi, namely Colletotrichum acutatum and Cladosporium fulvum. Pseudomonas drechsleri exhibited resistance to the widely used antifungal agent nystatin at a concentration of 2 μg per well and both Didymella bryoniae and Phytophthora capsici, along with Pseudomonas drechsleri, demonstrated resistance to synthesized platinum nanoparticles (PtNPs). Both C. acutatum and C. fulvum exhibited an inhibition zone when exposed to various concentrations of PtNPs. In order to evaluate the efficacy of antifungal agents against Aspergillus parasiticus and Aspergillus flavus, Deepika et al., (Godugu & Beedu, 2018) conducted a study to assess the persistence of biopolymer-mediated synthesized Pt platinum nanocomposites (referred to as GKPtNPs). The percentage of inhibition of fungal cells was observed to follow a dose-dependent pattern, with greater efficacy against Aspergillus flavus in comparison to Aspergillus parasiticus. The antifungal activity of the nanocomposite was observed to induce outer membrane damage of the fungi, the initiation of oxidative stress triggering the production of ROS. This oxidative stress-induced mechanism subsequently causes detrimental effects on the fungal mycelial morphology and membrane, ultimately resulting in cellular damage and impeding fungal growth.

PtNPs in Cancer Therapy Cancer, a complex and multifaceted disease, has emerged as the leading cause of human mortality, surpassing even infectious diseases (Sung et  al., 2021). Conventional chemotherapeutic agents, including anti-metabolites and alkylating agents, are known to elicit a multitude of adverse effects in patients. Henceforth, the

54

S. S. Samhitha et al.

scientific community has exhibited a keen interest in the utilization of targeted therapy as a means to mitigate the adverse effects associated with conventional treatment modalities (Gao & Dong, 2020). Platinum exhibits remarkable potential in combating cancer (Reedijk, 1987). PtNPs exhibit distinct functional characteristics when compared to platinum-containing drugs. The cellular uptake of PtNPs is facilitated through two primary mechanisms: passive diffusion and endocytosis. The extent of cytotoxicity induced by PtNPs is contingent upon various factors, including their size, concentration, and duration of incubation. In their study, Baskaran et al., (2017) employed Streptomyces spp. as a means to synthesize spherical PtNPs with an average size ranging from 20 to 50 nanometers. An in  vitro cytotoxicity analysis was performed using the 3-(4, 5-dimethyl-2-­ thiazolyl)-2, 5-diphenyl-tetrazolium assay to evaluate the potential cytotoxic effects of PtNPs. The results revealed an inhibitory concentration (IC50) of 31.2 μg/mLl against MCF-7 breast cancer cells. In a study conducted by Alshatwi et al. (2015), platinum nanoparticles were synthesized through the utilization of tea polyphenol (TPP) as both a surface modification and reducing agent, which yielded flower-­ shaped TTP@Pt nanoparticles with a size range of 30–60 nm. Cervical cancer cells (SiHa) were subjected to treatment with TPP@Pt in different dosages. The proliferation of SiHa cells was observed to be inhibited upon treatment with TPP@Pt in a cell culture setting, resulting in chromatin condensation and nuclear fragmentation. The administration of TPP@Pt was found to induce cell cycle arrest specifically in the G2/M stage, thereby preventing the progression of cells through this critical phase of the cell cycle. Additionally, TPP@Pt treatment was observed to lead to sub-G0 cell death, indicating a significant decrease in cell viability, thus indicating that TPP@Pt has the potential to serve as a therapeutic intervention for cervical cancer. Doxorubicin (DOX), a major clinical chemotherapeutic drug, is often studied for combination therapy (Zhao et al., 2015). Combination therapy of chemotherapeutic medicines and NPs affects several pathways, creating a synergistic impact that overcomes drug resistance and reduces side effects. Gurunathan et al. (2019a) examined the anti-tumor effect of DOX and PtNPs in human bone osteosarcoma epithelial cells. Using tangeretin, a pentamethoxyflavone, they made PtNPs with thermal stability, non-toxicity, and thermoplasmonic characteristics. DOX and PtNPs dose dependently inhibited human bone OS epithelial cells (U2OS) growth and viability and enhanced lactate dehydrogenase release, followed by mitochondrial malfunction. Lower antioxidant levels confirmed that oxidative stress causes genotoxicity and cytotoxicity. DOX + PtNPs also increased 8-oxo-G and 8-oxo-dG levels, DNA damage, and DNA repair gene expression. Fu et al., (2020) used PF127 (pluronic F127) to make mesoporous PtNPs. The platinum surface was coated with polyethylene glycol (PEG) (PEG@Pt), and then DOX was introduced, it was electrostatically adsorbed to create PEG@Pt/ DOX.  PEG@Pt/DOX released DOX predictably in pH  5.5 phosphate-buffered saline (PBS). Confocal imaging demonstrated that DOX-resistant breast carcinoma cells (MCF-7/ADR) took up PEG@Pt/DOX.  After 24  h, DOX was in the cell nucleus and cytoplasm. Flow cytometry and transmission electron microscopy

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral…

55

(TEM) verified cell uptake. When treated with an 808 nm laser, DOXox doses of 8 μg/mL or higher destroyed 84% of tumor cells. MCF-7/ADR cells responded better to combination therapy than wild-type MCF-7 cells. The multifunctional nanoplatform PEG@Pt/DOX could treat drug-resistant cancer cells with photothermal and chemotherapeutic drugs. PtNPs and platinum-based anticancer medicines can break DNA strands inside cells (Yamagishi et  al., 2013b). PtNPs can also scavenge hydrogen peroxide and superoxide and function as cancer theranostics due to their imaging ability (Park et  al., 2010). PtNPs’ cytotoxicity limits their usage in medicine and healthcare. Therefore, creating and testing more biocompatible PtNPs for cancer treatment is a big issue. Poor circulation times and low tumor tissue permanence of nano-drug conjugates and NPs may restrict nanomedicine‘s cancer efficacy (Fig. 1). Mukherjee et al., produced colloidal PEGylated PtNPs at room temperature via the borohydride reduction. PtNPs were biocompatible in chicken egg embryos and normal cell lines in vitro (Mukherjee et al., 2020). PtNPs-DOX inhibited B16F10 and A549 tumor cell proliferation in numerous in  vitro experiments. Annexin-V staining showed that PtNPs-DOX caused tumor cell death. In a mouse model of subcutaneous melanoma, intraperitoneal (IP) PtNPs-DOX suppressed tumor growth more than the free medication. Western blotting and immunofluorescence showed decreased Ki-67 and SOX2 proliferation markers and enhanced p53 expression in malignant melanoma, confirming anti-tumor efficacy. Platinum nanoparticles have emerged as a highly promising approach in the field of cancer treatment since they possess the potential to induce cancer cell death through several pathways, while concurrently enhancing the delivery and effectiveness of traditional chemotherapeutic agents. With the advancement of research and the continuous development of technology, platinum nanoparticles have emerged as a promising avenue for transforming the field of cancer therapy. These nanoparticles provide the potential to revolutionize treatment alternatives by enabling more precise targeting, enhanced efficiency, and tailored approaches.

Toxicity Effects Toxicity analysis is typically conducted through two primary methodologies, namely, in vivo and in vitro approaches. The methods employed in toxicity assessment vary depending on the specific system under investigation. In previous investigations, several studies have been conducted to examine the toxicity of NPs based on their size. These studies have focused on a range of metallic NPs, employing diverse methodologies and experimental approaches. Various metallic NPs have been utilized in the field of biomedical applications. Notably, Au and Ag NPs have been extensively employed in nanotoxicology studies. However, there is a scarcity of research focusing on the cytotoxicity of PtNPs. Numerous metallic NPs have been demonstrated to release ions inside of cells for potential action, however, there is currently no conclusive proof that the release

56

S. S. Samhitha et al.

Fig. 1  Diagrammatic sketch representing the possible mechanism of platinum nanoparticle-­ induced cytotoxicity in cancer cell lines. (Jan et al., 2021)

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral…

57

of platinum ions from PtNPs causes cell damage (Pelka et al., 2009). The impact of PtNPs on biological systems appears to be dependent on their size. Specifically, PtNPs measuring 8 nm in diameter did not exhibit any detrimental effects. However, PtNPs of 1 nm induce a dose-dependent cytotoxicity toward renal cells (Yamagishi et al., 2013a). PtNPs with a size of 6 nm were found to reduce genotoxic effects and metabolic activity without altering the morphology and migration capacity of primary keratinocytes. On the other hand, PtNPs with a size of 57 nm were found to be less harmful to keratinocytes compared to the smaller nanoparticles (Konieczny et al., 2013). The cytotoxic properties of PtNPs were investigated by employing tea-capped PtNPs in SiHa cervical cancer cells, indicating that the presence of tea-capped PtNPs had an impact on various cellular aspects, including cell survival, nuclear morphology, and cell cycle distribution also resulting in the suppression of proliferation of SiHa cells (De Vos, 1978). Asharani et al., (2009) observed that polyvinyl-­ coated PtNPs with a size range of between 5–8 nm, were able to penetrate the human cells by the process of diffusion. This penetration resulted in many effects, including an elevation in DNA damage, suppression of cell proliferation, and the initiation of p21 activation. Consequently, these cellular responses led to growth arrest mediated by proliferating cell nuclear antigen and ultimately resulted in apoptosis. Pomegranate extract-synthesized PtNPs decreased MCF-7 cell viability and increased apoptosis and DNA damage (Şahin et al., 2018). Two different types of PtNPs-NG-Pt NPs and MG-Pt NPS, with average sizes of 15 nm and 8.5 nm, respectively, decreased cell viability and increased the ROS generation in C2C12 cells. PtNPs also upregulated caspases 3 and 9 and proinflammatory proteins such as TNF-∝, TGF-β, and NF-κB. Smaller PtNPs increased cytotoxicity (Subramaniyan et  al., 2018). Gurunathan et  al., (2019b) reported that PtNps functionalized with apigenin demonstrated potential cytotoxic effects, genotoxic effects, and proinflammatory responses in a human monocytic cell line known as THP-1 through an increase in lactate dehydrogenase levels, generation of ROS, and the production of malondialdehyde, nitric oxide, and carbonylated proteins. Additionally, the functionalized PtNps were found to enhance apoptosis and oxidative DNA damage. In conclusion, the presence of PtNPs resulted in an elevation in the levels of several proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, tumor necrosis factor-α (TNF-α), granulocyte–macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein 1 (MCP-1). Furthermore, it has been extensively validated that PtNPs possess the ability to elicit cytotoxic effects in both cancerous and noncancerous cells.

Coronavirus Disease 2019 (COVID-19) PtNPs are used in many sensors for the detection of COVID-19. Clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) systems are adaptive immune systems observed in archaea and bacteria that naturally protect them

58

S. S. Samhitha et al.

from viruses and plasmids (Sorek et al., 2013). CRISPR RNAs (crRNAs) may identify and disintegrate complementary nucleic acid targets when combined with Cas endonucleases (Liu et al., 2019). CRISPR types III, V, and VI RNA-guided nucleases (Cas12, Cas13, and Cas14) also show collateral target-activated, nonspecific single-stranded nucleic acid hydrolysis activity (collateral cleavage), which broadens nucleic acid detection options. In their study, Liang et al., (2022) conducted the synthesis of a CRISPR/Cas12a-based test to advance the development of optical density biosensing systems (OD-CRISPR). The primary objective of this research was to detect SARS-CoV-2 RNA using a colorimetric biosensor that relies on the optical density (OD) transducer. The transducer is fabricated using a PtNPs probe that is functionalized with non-specific single-stranded DNA, transforming the process of target recognition into an optical density signal that can be easily measured using a cost-effective microplate reader. The OD-CRISPR has 79.17% sensitivity and 100% specificity, making it a potential nucleic acid screening diagnostic tool. The detection of the COVID-19 virus nucleocapsid protein was achieved using a biosensor developed by Tian et al., (2021). The biosensor-integrated electrochemical methodologies with the use of metal-organic frameworks (MOFs) called MIL-53 were decorated with Au@Pt nanoparticles and enzymes to detect SARS-CoV-2 nucleocapsid protein (2019-nCoV-NP) through the co-catalysis of nanomaterials, horseradish peroxidase (HRP), and G-quadruplex DNAzyme. The utilization of two distinct aptamers (N48 and N61) has been implemented in order to achieve selective binding with the target nucleocapsid protein. HRP and hemin/G-quadruplex DNAzyme were used to decorate Au@Pt/MIL-53 (Al) nanomaterial composites as signal nanoprobes. The aptasensor signal was amplified by the nanoprobe, which co-catalyzed hydroquinone oxidation in hydrogen peroxide. The GE surface was used to create the aptamer-protein-nanoprobe sandwich electrochemical detection system. This aptasensor could detect 2019-nCoV-NP within a wide linear range of 0.025–50 ng mL−1, with a detection limit of 8.33 pg mL−1. This aptasensor has exceptional sensitivity, selectivity, and reliability for early COVID-19 diagnosis. The integration of COVID-19 antibodies with graphite oxide field-effect transistors (GO-FET) was conducted by Wasfi et al., (2022) in order to enable the real-time detection of spike protein antigens. In this study, a novel approach was employed to enhance the selectivity and specificity of magnetic spike antibodies targeting the COVID-19 spike protein. A graphite oxide channel was utilized as a platform, connecting two gold electrodes, to serve as an anchor for the antibodies. This strategic design aimed to maximize the binding efficiency and accuracy of the antibodies, thereby facilitating effective detection and identification of the COVID-19 spike protein. The GO-FET biosensor underwent additional patterning with platinum– palladium bimetallic nanoparticles in order to enhance its sensitivity. The biosensor’s limit of detection (LOD) was determined to be 1  fg/mL when tested in a solution of phosphate-buffered saline.

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral…

59

Future Perspective PtNPs are well recognized as significant contributors in diverse domains of scientific research and technological advancements. Due to their remarkable features, they have garnered considerable attention in the biomedical area. This has led to their potential utilization as pharmaceutical agents, nano-diagnostic tools, and targeted drug delivery vehicles. Pt-based materials have been extensively utilized in clinical research for a considerable duration to address the adverse effects associated with chemotherapy and radiation therapy. Hence, the diagnostic and medical sectors are currently investigating the potential utilization of PtNPs as an advanced kind of anticancer treatment agent. Despite the high efficacy and low concentrations of biologically prepared nanomaterials, there are still several factors that must be taken into account for the clinical application of PtNPs. These factors include the source of raw materials, the production method, stability, solubility, biodistribution, controlled release, accumulation, cell-specific targeting, and potential toxicological issues in humans. In addition, it is imperative to address the challenges associated with exclusive multidrug resistance by developing multifunctional PtNPs that can serve as diagnostic and targeting tools, as well as nanocarriers and phototherapeutic agents. The present focus of molecular medicine revolves around the advancement of innovative tools that can effectively facilitate early-stage disease diagnosis and maintain long-term functionality within the cellular system. The potential incorporation of nanomaterials, particularly PtNPs, holds promise for expanding the scope of the theragnostic platform, a novel approach that integrates therapeutic and diagnostic functionalities. This integration has the potential to streamline and expedite the diagnostic procedures, while also minimizing invasiveness.

Conclusion The utilization of PtNPs with antibacterial and antifungal properties, has shown promising potentials in combating microbial infections. The diminutive dimensions and expansive surface area of these entities facilitate their engagement with microbial cells, thereby perturbing the integrity of cell membranes and impeding cellular proliferation. PtNPs also hold great promise in the field of cancer therapy as they can be used as drug delivery carriers, targeted agents, or for localized hyperthermia. PtNPs can enhance the efficacy of cancer treatments, minimize side effects, and improve the overall therapeutic outcome. However, challenges remain in terms of precise targeting, optimizing the therapeutic dosage, and understanding the long-­ term effects on healthy tissues. While PtNPs have demonstrated reasonable biocompatibility in many instances, concerns about their potential toxicity persist. As with any nanomaterial, thorough toxicological studies are necessary to ensure the safe use of PtNPs in various applications. Factors such as nanoparticle size, surface coatings, exposure routes, and accumulation in tissues require careful evaluation to

60

S. S. Samhitha et al.

mitigate potential adverse effects. Further investigation is required in order to explore the antiviral properties of PtNPs such as antiviral efficacy and underlying mechanisms as the existing literature is currently limited in scope and depth. Acknowledgements  We thank the National Research and Development Agency of Chile (ANID) for the resources granted by Becas Doctorado Nacional Folio 21221394 and also the Programa Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) de la Agencia Nacional de Investigación y Desarrollo (FONDECYT Project No 3200832), Chile.

References Abed, A., Derakhshan, M., Karimi, M., Shirazinia, M., Mahjoubin-Tehran, M., Homayonfal, M., Hamblin, M.  R., Mirzaei, S.  A., Soleimanpour, H., Dehghani, S., Dehkordi, F.  F., & Mirzaei, H. (2022). Platinum nanoparticles in biomedicine: Preparation, anti-cancer activity, and drug delivery vehicles. Frontiers in Pharmacology, 13, 1–23. https://doi.org/10.3389/ fphar.2022.797804 Al-Radadi, N. S. (2019). Green synthesis of platinum nanoparticles using Saudi’s Dates extract and their usage on the cancer cell treatment. Arabian Journal of Chemistry, 12(3), 330–349. https://doi.org/10.1016/J.ARABJC.2018.05.008 Alshatwi, A. A., Athinarayanan, J., & Vaiyapuri Subbarayan, P. (2015). Green synthesis of platinum nanoparticles that induce cell death and G2/M-phase cell cycle arrest in human cervical cancer cells. Journal of Materials Science: Materials in Medicine, 26(1), 1–9. https://doi. org/10.1007/S10856-­014-­5330-­1/METRICS Asharani, P. V., Xinyi, N., Hande, M. P., & Valiyaveettil, S. (2009). DNA damage and p53-­mediated growth arrest in human cells treated with platinum nanoparticles. Nanomedicine (London), 5(1), 51–64. https://doi.org/10.2217/NNM.09.85 Ayaz Ahmed, K. B., Raman, T., & Anbazhagan, V. (2016). Platinum nanoparticles inhibit bacteria proliferation and rescue zebrafish from bacterial infection. RSC Advances, 6(50), 44415–44424. https://doi.org/10.1039/C6RA03732A Bashir Wani, R., Kumar Dwivedi, D., Rewa, I., & Pradesh, M. (2023). Antibacterial activity of platinum nanoparticles using leaf extracts of cinnamomum camphora: An eco-friendly approach. Journal of Pharmaceutical Negative Results, 13, 7260–7269. https://doi.org/10.47750/ PNR.2022.13.S09.853 Baskaran, B., Muthukumarasamy, A., Chidambaram, S., Sugumaran, A., Ramachandran, K., & Manimuthu, T.  R. (2017). Cytotoxic potentials of biologically fabricated platinum nanoparticles from Streptomyces sp. on MCF-7 breast cancer cells. IET Nanobiotechnology, 11(3), 241–246. https://doi.org/10.1049/IET-­NBT.2016.0040 Cheng, H., Xi, C., Meng, X., Hao, Y., Yu, Y., & Zhao, F. (2009). Polyethylene glycol-stabilized platinum nanoparticles: The efficient and recyclable catalysts for selective hydrogenation of o-chloronitrobenzene to o-chloroaniline. Journal of Colloid and Interface Science, 336(2), 675–678. https://doi.org/10.1016/J.JCIS.2009.04.076 Chwalibog, A., Sawosz, E., Hotowy, A., Szeliga, J., Mitura, S., Mitura, K., Grodzik, M., Orlowski, P., & Sokolowska, A. (2010). Visualization of interaction between inorganic nanoparticles and bacteria or fungi. International Journal of Nanomedicine, 5(1), 1085–1094. https://doi. org/10.2147/IJN.S13532 De Vos, D. (1978). Platinum complexes as anticancer agent. Chemisch Weekblad, 74, 713. https:// doi.org/10.2174/157489206775246458 Fu, B., Dang, M., Tao, J., Li, Y., & Tang, Y. (2020). Mesoporous platinum nanoparticle-based nanoplatforms for combined chemo-photothermal breast cancer therapy. Journal of Colloid and Interface Science, 570, 197–204. https://doi.org/10.1016/J.JCIS.2020.02.051

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral…

61

Gangula, A., Podila, R., Ramakrishna, M., Karanam, L., Janardhana, C., & Rao, A. M. (2011). Catalytic reduction of 4-nitrophenol using biogenic gold and silver nanoparticles derived from breynia rhamnoides. Langmuir, 27(24), 15268–15274. https://doi.org/10.1021/LA2034559/ SUPPL_FILE/LA2034559_SI_001.PDF Gao, X., & Dong, Q. Z. (2020). Advance in metabolism and target therapy in breast cancer stem cells. World Journal of Stem Cells, 12(11), 1295–1306. https://doi.org/10.4252/WJSC.V12. I11.1295 Godugu, D., & Beedu, S. R. (2018). Biopolymer-mediated synthesis and characterisation of platinum nanocomposite and its anti-fungal activity against A. parasiticus and A. flavus. Micro & Nano Letters, 13(10), 1491–1496. https://doi.org/10.1049/MNL.2018.5097 Gurunathan, S., Jeyaraj, M., Kang, M.  H., & Kim, J.  H. (2019a). Tangeretin-assisted platinum nanoparticles enhance the apoptotic properties of doxorubicin: Combination therapy for osteosarcoma treatment. Nanomaterials (Basel, Switzerland), 9(8). https://doi.org/10.3390/ NANO9081089 Gurunathan, S., Jeyaraj, M., Kang, M.  H., & Kim, J.  H. (2019b). The effects of Apigenin-­ biosynthesized ultra-small platinum nanoparticles on the human monocytic THP-1 cell line. Cells, 8(5), 444. https://doi.org/10.3390/CELLS8050444 Hashimoto, M., Yamaguchi, S., Sasaki, J. I., Kawai, K., Kawakami, H., Iwasaki, Y., & Imazato, S. (2016). Inhibition of matrix metalloproteinases and toxicity of gold and platinum nanoparticles in L929 fibroblast cells. European Journal of Oral Sciences, 124(1), 68–74. https://doi. org/10.1111/EOS.12235 Jan, H., Khan, M. A., Usman, H., Shah, M., Ansir, R., Faisal, S., Ullah, N., & Rahman, L. (2020). The Aquilegia pubiflora (Himalayan columbine) mediated synthesis of nanoceria for diverse biomedical applications. RSC Advances, 10(33), 19219–19231. https://doi.org/10.1039/ D0RA01971B Jan, H., Gul, R., Andleeb, A., Ullah, S., Shah, M., Khanum, M., Ullah, I., Hano, C., & Abbasi, B. H. (2021). A detailed review on biosynthesis of platinum nanoparticles (PtNPs), their potential antimicrobial and biomedical applications. Journal of Saudi Chemical Society, 25(8), 101297. https://doi.org/10.1016/J.JSCS.2021.101297 Jeyaraj, M., Gurunathan, S., Qasim, M., Kang, M.  H., & Kim, J.  H. (2019). A comprehensive review on the synthesis, characterization, and biomedical application of platinum nanoparticles. Nanomaterials, 9(12). https://doi.org/10.3390/NANO9121719 Johnstone, T. C., Suntharalingam, K., & Lippard, S. J. (2016). The next generation of platinum drugs: Targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs. Chemical Reviews, 116(5), 3436–3486. https://doi.org/10.1021/ACS.CHEMREV.5B00597/ASSET/IMAGES/ LARGE/CR-­2015-­00597W_0004.JPEG Ke, X., Bittencourt, C., Bals, S., & Van Tendeloo, G. (2013). Low-dose patterning of platinum nanoclusters on carbon nanotubes by focused-electron-beam-induced deposition as studied by TEM. Beilstein. Journal of Nanotechnology, 4(1), 77–86. https://doi.org/10.3762/BJNANO.4.9 Konieczny, P., Goralczyk, A.  G., Szmyd, R., Skalniak, L., Koziel, J., Filon, F.  L., Crosera, M., Cierniak, A., Zuba-Surma, E.  K., Borowczyk, J., Laczna, E., Drukala, J., Pyza, E., Semik, D., Woznicka, O., Klein, A., & Jura, J. (2013). Effects triggered by platinum nanoparticles on primary keratinocytes. International Journal of Nanomedicine, 8, 3963–3975. https://doi. org/10.2147/IJN.S49612 Kubik, T., Bogunia-Kubik, K., & Sugisaka, M. (2016). Nanotechnology on duty in medical applications. Current Pharmaceutical Biotechnology, 6(1), 17–33. https://doi. org/10.2174/1389201053167248 Kweskin, S. J., Rioux, R. M., Habas, S. E., Komvopoulos, K., Yang, P., & Somorjai, G. A. (2006). Carbon monoxide adsorption and oxidation on monolayer films of cubic platinum nanoparticles investigated by infrared-visible sum frequency generation vibrational spectroscopy. Journal of Physical Chemistry B, 110(32), 15920–15925. https://doi.org/10.1021/JP062418A/ ASSET/IMAGES/LARGE/JP062418AF00007.JPEG

62

S. S. Samhitha et al.

Liang, J., Teng, P., Hu, L., He, G., Song, Q., Zhang, Y., Peng, B., Li, G., Xiao, W., Cao, D., & Tang, Y. (2022). Platinum nanoparticles (PtNPs)-based CRISPR/Cas12a platform for detection of nucleic acid and protein in clinical samples. Analytica Chimica Acta, 1225, 340203. https:// doi.org/10.1016/j.aca.2022.340203 Liu, J.-J., Orlova, N., Oakes, B. L., Ma, E., Spinner, H. B., Baney, K. L. M., Chuck, J., Tan, D., Knott, G. J., Harrington, L. B., Al-Shayeb, B., Wagner, A., Brötzmann, J., Staahl, B. T., Taylor, K. L., Desmarais, J., Nogales, E., & Doudna, J. A. (2019). CasX enzymes comprise a distinct family of RNA-guided genome editors. Nature, 566(7743), 218–223. https://doi.org/10.1038/ s41586-­019-­0908-­x Liu, J., Cao, R., Xu, M., Wang, X., Zhang, H., Hu, H., Li, Y., Hu, Z., Zhong, W., & Wang, M. (2020). Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-­ CoV-­2 infection in vitro. Cell Discovery, 6(1), 16. https://doi.org/10.1038/s41421-­020-­0156-­0 López-Goerne, T., de la Rosa-Gutiérrez, G., Padilla-Godínez, F. J., Bustos-Martínez, J., López, S., Xoconostle-Cázares, B., & de la Rosa, J. M. (2022). Inhibition of Influenza A (H1N1) virus infection by Pt/TiO2-SiO2 Bionanocatalysts. Current Nanoscience, 18(6), 733–742. https://doi. org/10.2174/1573413717666211118110801 Mohammadi, H., Abedi, A., Akbarzadeh, A., Mokhtari, M. J., Shahmabadi, H. E., Mehrabi, M. R., Javadian, S., & Chiani, M. (2013). Evaluation of synthesized platinum nanoparticles on the MCF-7 and HepG-2 cancer cell lines. International Nano Letters, 3(1), 1–5. https://doi.org/1 0.1186/2228-­5326-­3-­28 Mohanraj, V. J., & Chen, Y. (2006). Nanoparticles – A review. Tropical Journal of Pharmaceutical Research, 5(1), 561–573. https://doi.org/10.4314/TJPR.V5I1.14634 Morad, R., Akbari, M., Rezaee, P., Koochaki, A., Maaza, M., & Jamshidi, Z. (2021). First principle simulation of coated hydroxychloroquine on Ag, Au and Pt nanoparticles. Scientific Reports, 11(1), 2131. https://doi.org/10.1038/s41598-­021-­81617-­6 Mukherjee, S., Kotcherlakota, R., Haque, S., Bhattacharya, D., Kumar, J. M., Chakravarty, S., & Patra, C.  R. (2020). Improved delivery of doxorubicin using rationally designed PEGylated platinum nanoparticles for the treatment of melanoma. Materials Science and Engineering: C, 108, 110375. https://doi.org/10.1016/j.msec.2019.110375 Niesz, K., Grass, M., & Somorjai, G.  A. (2005). Precise control of the Pt nanoparticle size by seeded growth using EO 13PO30EO13 triblock copolymers as protective agents. Nano Letters, 5(11), 2238–2240. https://doi.org/10.1021/NL051561X/ASSET/IMAGES/MEDIUM/ NL051561XN00001.GIF Nishanthi, R., Malathi, S., John Paul, S., & Palani, P. (2019). Green synthesis and characterization of bioinspired silver, gold and platinum nanoparticles and evaluation of their synergistic antibacterial activity after combining with different classes of antibiotics. Materials Science and Engineering: C, 96, 693–707. https://doi.org/10.1016/J.MSEC.2018.11.050 Park, E. J., Kim, H., Kim, Y., & Park, K. (2010). Intratracheal instillation of platinum nanoparticles may induce inflammatory responses in mice. Archives of Pharmacal Research, 33(5), 727–735. https://doi.org/10.1007/S12272-­010-­0512-­Y Paschos, O., Choi, P., Efstathiadis, H., & Haldar, P. (2008). Synthesis of platinum nanoparticles by aerosol assisted deposition method. Thin Solid Films, 516(12), 3796–3801. https://doi. org/10.1016/J.TSF.2007.06.123 Pelka, J., Gehrke, H., Esselen, M., Türk, M., Crone, M., Bräse, S., Muller, T., Blank, H., Send, W., Zibat, V., Brenner, P., Schneider, R., Gerthsen, D., & Marko, D. (2009). Cellular uptake of platinum nanoparticles in human colon carcinoma cells and their impact on cellular redox systems and DNA integrity. Chemical Research in Toxicology, 22(4), 649–659. https://doi.org/10.1021/ TX800354G/ASSET/IMAGES/MEDIUM/TX-­2008-­00354G_0001.GIF Ramkumar, V. S., Pugazhendhi, A., Prakash, S., Ahila, N. K., Vinoj, G., Selvam, S., Kumar, G., Kannapiran, E., & Rajendran, R. B. (2017). Synthesis of platinum nanoparticles using seaweed Padina gymnospora and their catalytic activity as PVP/PtNPs nanocomposite towards biological applications. Biomedicine & Pharmacotherapy, 92, 479–490. https://doi.org/10.1016/J. BIOPHA.2017.05.076

Platinum Nanoparticles in Biomedical Applications: Antibacterial and Antiviral…

63

Reedijk, J. (1987). The mechanism of action of platinum antitumor drugs. Pure and Applied Chemistry, 59(2), 181–192. https://doi.org/10.1351/PAC198759020181/ MACHINEREADABLECITATION/RIS Şahin, B., Aygün, A., Gündüz, H., Şahin, K., Demir, E., Akocak, S., & Şen, F. (2018). Cytotoxic effects of platinum nanoparticles obtained from pomegranate extract by the green synthesis method on the MCF-7 cell line. Colloids and Surfaces B: Biointerfaces, 163, 119–124. https:// doi.org/10.1016/J.COLSURFB.2017.12.042 Salem, S. S., & Fouda, A. (2021). Green synthesis of metallic nanoparticles and their prospective biotechnological applications: An overview. Biological Trace Element Research, 199(1), 344–370. https://doi.org/10.1007/S12011-­020-­02138-­3 Schmidt, T.  J., Gasteiger, H.  A., & Behm, R.  J. (1999). Rotating disk electrode measurements on the CO tolerance of a high-surface area Pt/Vulcan carbon fuel cell catalyst. Journal of the Electrochemical Society, 146(4), 1296–1304. https://doi.org/10.1149/1.1391761 Shiny, P.  J., Mukherjee, A., & Chandrasekaran, N. (2014). Haemocompatibility assessment of synthesised platinum nanoparticles and its implication in biology. Bioprocess and Biosystems Engineering, 37(6), 991–997. https://doi.org/10.1007/S00449-­013-­1069-­1/FIGURES/7 Smith, D. M., Simon, J. K., & Baker, J. R. (2013). Applications of nanotechnology for immunology. Nature Reviews Immunology, 13(8), 592–605. https://doi.org/10.1038/nri3488 Sorek, R., Lawrence, C.  M., & Wiedenheft, B. (2013). CRISPR-mediated adaptive immune Systems in Bacteria and Archaea. Annual Review of Biochemistry, 82(1), 237–266. https://doi. org/10.1146/annurev-­biochem-­072911-­172315 Subramaniyan, S. B., Ramani, A., Ganapathy, V., & Anbazhagan, V. (2018). Preparation of self-­ assembled platinum nanoclusters to combat salmonella typhi infection and inhibit biofilm formation. Colloids and Surfaces B: Biointerfaces, 171, 75–84. https://doi.org/10.1016/J. COLSURFB.2018.07.023 Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians, 71(3), 209–249. https:// doi.org/10.3322/CAAC.21660 Taha, J. H., Abbas, N. K., & Al-Attraqchi, A. A. F. (2023). Synthesis and evaluation of platinum nanoparticles using F. Carica fruit extract and their antimicrobial activities. Baghdad Science Journal, 20(3 Suppl), 1146. https://doi.org/10.21123/bsj.2023.7294 Tahir, K., Nazir, S., Ahmad, A., Li, B., Khan, A. U., Khan, Z. U. H., Khan, F. U., Khan, Q. U., Khan, A., & Rahman, A. U. (2017). Facile and green synthesis of phytochemicals capped platinum nanoparticles and in vitro their superior antibacterial activity. Journal of Photochemistry and Photobiology B: Biology, 166, 246–251. https://doi.org/10.1016/J.JPHOTOBIOL.2016.12.016 Teranishi, T., Hosoe, M., Tanaka, T., & Miyake, M. (1999). Size control of monodispersed Pt nanoparticles and their 2D organization by electrophoretic deposition. Journal of Physical Chemistry B, 103(19), 3818–3827. https://doi.org/10.1021/JP983478M Tian, J., Liang, Z., Hu, O., He, Q., Sun, D., & Chen, Z. (2021). An electrochemical dual-aptamer biosensor based on metal-organic frameworks MIL-53 decorated with Au@Pt nanoparticles and enzymes for detection of COVID-19 nucleocapsid protein. Electrochimica Acta, 387, 138553. https://doi.org/10.1016/j.electacta.2021.138553 Velmurugan, P., Shim, J., Kim, K., & Oh, B. T. (2016). Prunus × yedoensis tree gum mediated synthesis of platinum nanoparticles with antifungal activity against phytopathogens. Materials Letters, 174, 61–65. https://doi.org/10.1016/J.MATLET.2016.03.069 Wasfi, A., Awwad, F., Qamhieh, N., Al Murshidi, B., Palakkott, A. R., & Gelovani, J. G. (2022). Real-time COVID-19 detection via graphite oxide-based field-effect transistor biosensors decorated with Pt/Pd nanoparticles. Scientific Reports, 12(1), 18155. https://doi.org/10.1038/ s41598-­022-­22249-­2 Williams, K. R., & Burstein, G. T. (1997). Low temperature fuel cells: Interactions between catalysts and engineering design. Catalysis Today, 38, 401–410.

64

S. S. Samhitha et al.

Yamagishi, Y., Watari, A., Hayata, Y., Li, X., Kondoh, M., Tsutsumi, Y., & Yagi, K. (2013a). Hepatotoxicity of sub-nanosized platinum particles in mice. Pharmazie, 68(3), 178–182. https://doi.org/10.1691/PH.2013.2141 Yamagishi, Y., Watari, A., Hayata, Y., Li, X., Kondoh, M., Yoshioka, Y., Tsutsumi, Y., & Yagi, K. (2013b). Acute and chronic nephrotoxicity of platinum nanoparticles in mice. Nanoscale Research Letters, 8(1), 1–7. https://doi.org/10.1186/1556-­276X-­8-­395 Zhao, Y., Chen, F., Pan, Y., Li, Z., Xue, X., Okeke, C. I., Wang, Y., Li, C., Peng, L., Wang, P. C., Ma, X., & Liang, X. J. (2015). Nanodrug formed by Coassembly of dual anticancer drugs to inhibit cancer cell drug resistance. ACS Applied Materials & Interfaces, 7(34), 19295–19305. https://doi.org/10.1021/ACSAMI.5B05347 Zheng, B., Kong, T., Jing, X., Odoom-Wubah, T., Li, X., Sun, D., Lu, F., Zheng, Y., Huang, J., & Li, Q. (2013). Plant-mediated synthesis of platinum nanoparticles and its bioreductive mechanism. Journal of Colloid and Interface Science, 396, 138–145. https://doi.org/10.1016/J. JCIS.2013.01.021 Zou, F., Zhou, J., Zhang, J., Li, J., Tang, B., Chen, W., Wang, J., & Wang, X. (2018). Functionalization of silk with in-situ synthesized platinum nanoparticles. Materials, 11(10), 1929. https://doi. org/10.3390/MA11101929

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential Applications Varaprasad Kokkarachedu, Karthikeyan Chandrasekaran, Natarajan Sisubalan, Tippabattini Jayaramudu, Arumugam Vijayan, and Rotimi Sadiku

Introduction The global healthcare industry has faced unprecedented challenges in recent years, owing to the emergence and rapid spread of infectious diseases (Karthikeyan et al., 2021). From bacterial infections that cause severe healthcare-associated infections to viral outbreaks, such as the coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need for effective strategies and materials to combat these pathogens (Ribas et  al., 2020). Traditional antimicrobial agents and disinfectants have V. Kokkarachedu (*) Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile e-mail: [email protected] K. Chandrasekaran Department of Chemical and Biochemical Engineering, Dongguk University, Seoul, Republic of Korea N. Sisubalan Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand T. Jayaramudu Department of Biomedical Engineering, University of Memphis, Memphis, TN, USA A. Vijayan Department of Microbiology, SRM Institute of Science and Technology, Tiruchirappalli, TN, India R. Sadiku Department of Chemical, Metallurgical & Materials Engineering, Institute of Nano Engineering Research (INER), Tshwane University of Technology, Pretoria West Campus, Pretoria, Republic of South Africa © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_4

65

66

V. Kokkarachedu et al.

their limitations, including toxicity, development of resistance, and environmental concerns. As a result, researchers and healthcare professionals have been exploring novel materials with enhanced antibacterial, antiviral, and other healthcare applications. Silicon dioxide (SiO2) has garnered significant attention as a multifunctional material with tremendous potential in healthcare settings (Yang et al., 2020). It possesses inherent properties that make it suitable for various medical applications, including its antibacterial and antiviral capabilities, biocompatibility, and environmental sustainability. SiO2 can be fabricated into nanoparticles, films, coatings, and composite materials, enabling its integration into a wide range of medical devices, personal protective equipment (PPE), drug delivery systems, and surface coatings (Bhuiyan et al., 2020; Geyao et al., 2020; Li et al., 2016; Yang et al., 2020). The primary objective of this book chapter is to provide a comprehensive overview of SiO2 and its applications in healthcare, with a particular focus on its antibacterial, antiviral, and other healthcare-related properties. By highlighting the advantages and challenges associated with SiO2 utilization, this chapter seeks to contribute to the advancement of healthcare materials and technologies. SiO2 possesses inherent properties that make it attractive for healthcare applications (Liu et al., 2022). Its chemical structure, physical characteristics, and surface properties play a vital role in determining its functionality. The understanding of the synthesis methods of SiO2 nanoparticles and films is crucial for the tailoring of its properties to suit specific healthcare needs. In addition, SiO2 has demonstrated significant antibacterial properties against various bacteria, including Gram-positive and Gram-negative strains (Bae et al., 2019). The mechanisms underlying the SiO2 antibacterial activity, involve physical disruption, reactive oxygen species (ROS) generation, and its interference with bacterial cell processes. In addition to its antibacterial properties, SiO2 exhibits antiviral capabilities against a broad range of viruses. SiO2 nanoparticles have shown inhibitory effects on viral particles by interfering with viral attachment, entry, and replication. SiO2-based materials find diverse applications in healthcare. They can be incorporated into medical devices, such as implants, wound dressings, and catheters, due to their antibacterial and antifouling properties (Jia et al., 2008). SiO2 potential for drug delivery systems, including targeted and controlled release systems, is also being explored. Furthermore, SiO2 can enhance the antimicrobial properties of various healthcare surfaces through surface coatings. Additionally, SiO2 has the potential to be incorporated into PPE, such as masks and gloves, to provide an added layer of protection against pathogens. While SiO2 holds great promise for healthcare applications, several challenges need to be addressed. Biocompatibility, stability, and scale-up production are crucial considerations in translating SiO2-based materials into clinical use. Future research and development efforts should focus on overcoming these challenges and exploring emerging trends and strategies, such as nanotechnology and surface modification techniques, to maximize the potential of SiO2 in healthcare. However, SiO2-based materials offer unique properties that make them attractive for use as antibacterial, antiviral  agent, and other healthcare applications. This chapter provides an introduction to SiO2 and its potential in healthcare, emphasizing its

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

67

antibacterial, antiviral, and multifunctional properties. By understanding the advantages and challenges associated with SiO2 utilization, this chapter aims to stimulate further research and development in this rapidly evolving field, ultimately leading to improved healthcare outcomes.

Advantages of SiO2 The advantages and benefits of SiO2 in antibacterial and antiviral applications: SiO2 has gained significant attention in the medical field due to its unique properties and  its potential to combat microbial infections. This chapter comprehensively, reviews the advantages of SiO2 in various antibacterial and antiviral applications. Biocompatibility  SiO2 demonstrates outstanding biocompatibility, thereby, facilitating favorable interactions with living tissues, while minimizing adverse reactions (Fu et al., 2020). When SiO2 degrades, it forms silicic acid (Si(OH)4), which is a naturally occurring compound found in the body and can be easily metabolized and eliminated (Jurkić et al., 2013). This degradation process of SiO2 does not typically cause adverse reactions or toxicity. Therefore, it exhibits the potential for biodegradability, enhancing its suitability for biomedical applications (Jaganathan & Godin, 2012). The exceptional biocompatibility of SiO2 is of paramount importance in medical contexts, ensuring that the human body efficiently tolerates SiO2-based antibacterial and antiviral materials without eliciting immune responses or toxic effects. This attribute is supported by extensive scientific research and serves as a fundamental criterion for successfully utilizing SiO2 in various biomedical applications. Antibacterial Activity  SiO2 has been shown to possess antimicrobial properties, which make it a promising material for various applications in healthcare and biomedicine (Tian & Liu, 2021). In addition, its derivative materials possess inherent antibacterial properties, which confer the ability to combat a diverse spectrum of bacterial strains. Furthermore, the surface properties of SiO2 can be precisely tailored to optimize its antimicrobial efficacy against both Gram-positive and Gram-­ negative bacteria, rendering it an attractive and versatile option for an array of antibacterial applications (Fonseca et al., 2022). These characteristics are rooted in the physicochemical interactions between SiO2 and bacterial cells, including surface charge, morphology, and the release of reactive oxygen species. Scientific investigations have demonstrated the capacity of SiO2-based materials to inhibit bacterial growth effectively, disrupt biofilm formation, and mitigate the development of antibiotic resistance, substantiating their potential for combating bacterial infections in diverse biomedical settings (Hetrick et  al., 2009). In addition, SiO2 nanoparticles can be designed to release nitric oxide, a potent antimicrobial agent. Nitric oxide has broad-spectrum activity against various bacteria, including antibiotic-­resistant strains. The release of nitric oxide from SiO2 nanoparticles enhances their antibacterial efficacy and can specifically target biofilm-associated bacteria.

68

V. Kokkarachedu et al.

Controlled Release  SiO2 nanoparticles offer a significant advantage through their ability to achieve controlled and sustained release of various antimicrobial agents (Hetrick et al., 2009; Zhang et al., 2013). This controlled release mechanism, allows for a prolonged and consistent antimicrobial effect, ensuring continuous protection against bacterial colonization and biofilm formation. By precisely engineering the properties of SiO2 nanoparticles, such as their size, surface characteristics, and composition, the release kinetics of diverse antimicrobial agents can be modulated to meet specific therapeutic requirements. This controlled release strategy enables targeted and localized delivery of antimicrobial agents, minimizing off-target effects while maximizing their efficacy against bacterial pathogens. By integrating different antimicrobial agents into SiO2 nanoparticles, such as antibiotics, metal ions, or other antimicrobial compounds, a synergistic effect can be achieved, further enhancing their antibacterial activity. The controlled release of these agents from SiO2 nanoparticles offers a promising approach for addressing challenges associated with the rapid degradation or inactivation of antimicrobial agents, extending their antimicrobial activity, and optimizing therapeutic outcomes. This advantageous feature, makes SiO2 nanoparticles a promising platform for the development of advanced antimicrobial strategies, particularly in combating biofilm-related infections where sustained antimicrobial action is crucial for effective treatment. Antiviral Activity  SiO2 nanoparticles have demonstrated promising antiviral activity against a wide range of viral strains, making them a potential tool in combating viral infections (Tng & Low, 2023). While the specific types of viruses tested may vary across studies, SiO2 nanoparticles have shown effectiveness against both enveloped and non-enveloped viruses (Hirao et al., 2023; Joe et al., 2014). Enveloped viruses, such as influenza viruses, herpesviruses, and coronaviruses (including SARS-CoV-2), possess a lipid envelope surrounding their viral particle. SiO2 nanoparticles can interact with and disrupt the integrity of this envelope, inhibiting viral entry into host cells and reducing infectivity (Hirao et  al., 2023). Non-­ enveloped viruses, such as noroviruses and adenoviruses, lack a lipid envelope but have a protein capsid that protects their genetic material (Heldt et al., 2017). SiO2 nanoparticles can directly interact with the viral capsid, leading to structural damage and inhibiting viral replication. It is important to note that the antiviral activity of SiO2 nanoparticles can be influenced by factors such as nanoparticle size, surface characteristics, and the targeted viral strains. However, their unique physicochemical properties enable interactions with viral particles, leading to the inhibition of viral replication and a reduction in infectivity. SiO2-based materials hold significant potential for applications in antiviral therapies and as coatings for medical devices, providing a means to mitigate viral infections and enhance overall health outcomes (Assis et al., 2021a). The interactions between SiO2 nanoparticles and viral particles, involve multiple mechanisms. First, the high surface area of SiO2 nanoparticles facilitates the adsorption of viral particles, preventing them from entering host cells and initiating infection. Additionally, SiO2 nanoparticles can interfere with the structural integrity of viral envelopes, impairing viral attachment and entry into host cells. This disruption of viral entry pathways contributes to the reduction in viral

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

69

infectivity. Furthermore, SiO2 nanoparticles can exhibit virucidal effects by inducing oxidative stress within viral particles. The nanoparticles can generate ROS upon exposure to light or other activating agents. These ROS possess potent antiviral properties, damaging viral nucleic acids, proteins, and lipid membranes. This oxidative damage hampers viral replication and renders the viruses non-infectious. The potential applications of SiO2-based materials in antiviral therapies are wide-­ ranging. They can be incorporated into drug delivery systems, enabling targeted and controlled release of antiviral agents to specific sites of infection. SiO2 nanoparticles can also be used as medical device surface coatings, inhibiting viral adhesion and transmission. This is particularly important in healthcare settings, where the risk of viral spread is a significant concern. In summary, SiO2 nanoparticles possess unique physicochemical properties that contribute to their promising antiviral activity. Their interactions with viral particles, inhibition of viral replication, and reduction in infectivity make them valuable tools for antiviral therapies and the mitigation of viral infections. The application of SiO2-based materials in healthcare, including drug delivery systems and medical device coatings, holds significant potential for improving health outcomes by combating viral infections and reducing their transmission. Resistance to Bacterial Adhesion  One of the key advantages of SiO2-based materials is their ability to resist bacterial adhesion. The nanostructured surface of SiO2 can prevent the attachment of bacteria, reducing the risk of biofilm formation and subsequent infections (Lozins et al., 2020). Long-lasting and Durable Effect  SiO2 coatings and nanoparticles exhibit long-­ lasting antibacterial and antiviral effects (Mussel-inspired degradable antibacterial polydopamine/silica nanoparticle for rapid hemostasis). Their stability and durability ensure sustained activity, making them suitable for applications like wound dressings and implantable devices. SiO2 is generally resistant to degradation but may gradually degrade under specific conditions. However, its controlled degradation is well-tolerated in biomedical applications, and its degradation products are biocompatible. SiO2 coatings enhance material durability, such as TiO2/SiO2 photocatalytic coatings maintaining self-cleaning effects (Khannyra et al., 2022). SiO2, also known as silicon dioxide or silica, has several advantages that make it a valuable material in various industries. Here are some of its advantages. SiO2 is abundant in nature and relatively inexpensive to produce compared to other materials with similar properties. This makes it a cost-effective choice for many applications. SiO2 has a high melting point (1713 °C) and can withstand high temperatures without undergoing significant structural changes (Ringdalen & Tangstad, 2016; Wan et  al., 2015). This makes it a  useful  tool in the  manufacturing of  high-­ temperature resistant materials, such as refractories, ceramics, and glass. SiO2 is highly resistant to chemical attack by acids, bases, and other corrosive substances. This makes it useful in chemical processing, water treatment, and other applications where chemical resistance is important. However, SiO2 is non-toxic and safe for use in humans and animals, making it an attractive alternative to other antibacterial and

70

V. Kokkarachedu et al.

antiviral agents that may have harmful side effects. In addition, it is easy to functionalize with various antibacterial and antiviral agents, allowing for the development of customized materials with specific properties.

The Disadvantages of SiO2 in Medical Applications While SiO2 has various advantages in medical applications, it is also essential to consider its disadvantages. Some of the disadvantages of SiO2 in medical applications, include: Slow Degradation  One of the disadvantages of SiO2 in medical applications, is its slow degradation rate. SiO2 is generally biocompatible and can degrade over time through hydrolysis or dissolution processes. However, in specific applications, where faster biodegradation is desired for controlled drug release or tissue regeneration, the slow degradation of SiO2 may not be ideal (Seré et al., 2018). Limited Drug Loading Capacity  SiO2 nanoparticles may have limited drug loading capacity; therefore, the structure can be modified to improve the drug loading (Seré et al., 2018). The loading efficiency of certain drugs onto SiO2 carriers may be lower than other nanoparticle systems, which could impact the effectiveness of drug delivery (Ways et al., 2020). Potential Toxicity  While SiO2 is generally considered biocompatible, concerns have been raised regarding potential toxicity associated with the size, shape, and surface characteristics of SiO2 nanoparticles (Zhang et al., 2022). Studies have suggested that very small nanoparticles can enter cells and induce adverse effects, which may raise long-term safety concerns (Agnihothram et al., 2016). Inflammatory Response  In some cases, SiO2 nanoparticles can trigger an inflammatory response in the body, primarily upon direct contact with immune cells or tissues (Ogawa et al., 2021). Factors, such as nanoparticle size, surface properties, and immune cell activation, play a role in the inflammatory response. Careful consideration of nanoparticle characteristics is essential to minimize potential adverse effects in biomedical and consumer applications (Ogawa et  al., 2021; Tsugita et al., 2017). Clearance Issues  SiO2 nanoparticles may face challenges in terms of clearance from the body. Prolonged circulation of nanoparticles can lead to potential accumulation in tissues, which may raise concerns about long-term biocompatibility (Agnihothram et al., 2016). Other Disadvantages  SiO2 nanoparticles can interact with proteins and other biological molecules, potentially altering their behavior and functionality. These interactions may impact the drug release kinetics or affect the intended biological targets. In addition, for certain drug delivery applications, SiO2 nanoparticles may not be the ideal carrier for specific drugs. Materials choice must be carefully considered to

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

71

ensure compatibility with the drug and the intended therapeutic effect. As with any material used in medical applications, it is essential to thoroughly investigate these disadvantages and carefully evaluate the specific requirements of each application to ensure the safe and effective use of SiO2-based materials.

Toxicity of SiO2 on Living Cells The potential toxicity of silica on living cells largely depends on the form and size of the particles as well as the duration and intensity of exposure. There are two types of silica particles based on their size: (a) Crystalline silica: Crystalline silica exists in the crystalline form, and it is of great concern due to its potential to cause health issues (Borm et  al., 2018). The three main types of crystalline silica are quartz, cristobalite, and tridymite. (b) Amorphous silica: Amorphous silica lacks a specific crystalline structure and it is generally considered to have lower toxicity when compared to the crystalline silica (Lee et al., 2020). Studies have shown that both crystalline and amorphous silica nanoparticles can cause genotoxic effects, such as DNA damage and chromosomal aberrations. However, the genotoxicity of crystalline silica is generally considered to be higher than that of amorphous silica (Lee et al., 2020). In terms of non-genotoxic effects, both types of silica nanoparticles can induce inflammation and oxidative stress in cells and tissues. Crystalline silica has been shown to have a higher potential for inducing fibrosis and lung cancer compared to amorphous silica. While amorphous silica is generally considered to have lower toxicity compared to crystalline silica, it is important to note that the toxicity of silica nanoparticles can vary depending on factors such as nanoparticle size, shape, surface area, and surface chemistry. Therefore, it is important to evaluate the toxicity of specific types of silica nanoparticles on a case-by-case basis. However, when silica particles come into contact with normal cells, such as those found in the respiratory system or skin, several biological responses can occur. The extent of these interactions depends on various factors, including the size, shape, and surface properties of the silica particles as well as the duration and concentration of exposure. Cellular Uptake and Internalization  Silica particles can be taken up by cells through various mechanisms, including endocytosis and phagocytosis. Once inside the cells, silica particles can interact with different intracellular components, leading to cellular responses. Inflammatory Response  One of the most prominent effects of silica exposure is the induction of inflammation. Silica particles can activate immune cells, such as macrophages, which recognize the particles as foreign invaders. This recognition triggers an inflammatory response, leading to the release of pro-inflammatory cytokines, chemokines, and other mediators. The chronic inflammation caused by silica exposure can contribute to tissue damage and remodeling.

72

V. Kokkarachedu et al.

Oxidative Stress  Silica particles can generate reactive oxygen species (ROS) within cells. ROS are highly reactive molecules, which can cause oxidative damage to cellular components, such as lipids, proteins, and DNA.  The accumulation of ROS can disrupt cellular functions and contribute to cellular dysfunction and injury. Cytotoxicity  Silica particles can directly damage cells and cause cell death. The cytotoxic effects may be related to the release of inflammatory mediators, ROS production, and disruption of cellular membranes or organelles. DNA Damage and Genotoxicity  Silica particles have the potential to cause DNA damage in exposed cells. This damage can lead to genetic mutations and alterations, which may contribute to the development of various diseases, including cancer. Activation of Fibrogenic Responses  Chronic exposure to silica is a significant risk factor for the development of silicosis, a progressive and irreversible lung disease. Silica particles can activate fibroblasts, leading to excessive deposition of collagen and fibrotic tissue in the lungs, impairing lung function over time. Epigenetic Changes  Emerging research suggests that silica exposure may induce epigenetic changes in cells, which can alter gene expression patterns without modifying the DNA sequence. These changes can have long-lasting effects on cellular behavior and may contribute to the development of diseases. It is important to note that the magnitude and severity of these cellular responses may vary depending on the context of exposure. Occupational settings with high levels of silica exposure pose a more significant risk compared to occasional or low-­ level environmental exposure. Additionally, individual susceptibility to silica toxicity can also play a role, with some individuals being more sensitive to silica’s effects than others. The understanding of the mechanisms by which silica interacts with normal cells, is essential for developing strategies to minimize the adverse health effects associated with exposure. Occupational safety guidelines and regulations aim to limit silica exposure and protect workers from potential health risks. In research and industry, efforts are ongoing to develop safer forms of silica and better understand the relationship between silica particles and cellular responses to ensure safe handling and usage.

Antibacterial Mechanism of SiO2 Nanoparticles Adsorption and Membrane Disruption  SiO2 nanoparticles possess a high surface area-to-volume ratio, which allows them to adsorb onto the surface of bacterial cells. The adsorption process involves electrostatic interactions between the nanoparticles and the bacterial membrane. Once adsorbed, the nanoparticles can interact with the lipid bilayer of the bacterial membrane. This interaction can d­ isrupt the integrity and structure of the membrane, compromising its barrier function. As a consequence, there is an increased permeability of the membrane, leading to the

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

73

leakage of essential cellular contents, such as ions and cytoplasmic molecules. The loss of these vital components severely affects the bacterial cell’s homeostasis and function, ultimately leading to cell death. Reactive Oxygen Species (ROS) Generation  SiO2 nanoparticles have the ability to generate ROS upon exposure to light or heat. These ROS are highly reactive molecules that include singlet oxygen, hydroxyl radicals, superoxide anions, and hydrogen peroxide. When SiO2 nanoparticles interact with environmental sources of light or heat, they undergo electronic transitions, leading to the generation of ROS. These ROS can induce oxidative stress within bacterial cells. Oxidative stress occurs when there is an imbalance between ROS generation and the cellular antioxidant defense mechanisms. The excess ROS can attack various biomolecules within the bacterial cell, including proteins, lipids, and DNA. This oxidative damage disrupts vital cellular processes, leading to cellular dysfunction and ultimately bacterial cell death. Intracellular Penetration  SiO2 nanoparticles possess unique properties that enable them to penetrate bacterial cells. These nanoparticles can be taken up by bacteria through various mechanisms, such as endocytosis or direct penetration through the cell membrane. Once inside the bacterial cell, the nanoparticles can exert their antibacterial effects from within the cytoplasm. Within the intracellular environment, the nanoparticles can disrupt vital cellular processes, such as DNA replication, protein synthesis, and energy production. They may interfere with enzymes and cellular machinery, leading to the inactivation of essential cellular functions. This disruption of intracellular processes eventually leads to bacterial cell death. The antibacterial mechanism of SiO2 nanoparticles involves multiple pathways, including adsorption and membrane disruption, ROS generation, and intracellular penetration. These mechanisms collectively contribute to the bactericidal activity of SiO2 nanoparticles and their potential applications as antimicrobial agents.  The understanding of the intricate interactions between SiO2 nanoparticles and bacterial cells, is crucial for the development of effective antibacterial strategies and the advancement of biomedical applications. Further research in this area holds promise for combating bacterial infections and improving public health.

Antiviral Mechanism of SiO2 Nanoparticles Viral Attachment Inhibition  SiO2 nanoparticles can interfere with the attachment of viruses to host cells. When viruses enter the body, they rely on specific interactions between viral surface proteins and host cell receptors to initiate infection. SiO2 nanoparticles can bind to these viral surface proteins or host cell receptors, blocking the viral attachment process. By preventing the initial attachment, SiO2 nanoparticles effectively reduce viral entry into host cells, thereby limiting viral infection and replication.

74

V. Kokkarachedu et al.

Viral Capsid Disruption  SiO2 nanoparticles can also interact with the protein coat or capsid of viruses. The viral capsid is a protective outer shell that encloses the viral genetic material. By interacting with the viral capsid, SiO2 nanoparticles can induce structural disruption and damage to the capsid proteins. This leads to the degradation or destabilization of the viral capsid, rendering the virus non-infectious and unable to enter host cells or replicate. ROS Generation and RNA/DNA Damage  Similar to the antibacterial mechanism, SiO2 nanoparticles can generate ROS upon exposure to light or heat. These ROS are highly reactive molecules, which can penetrate the viral structure. ROS can induce oxidative damage upon its  contact with the viral genetic material (RNA/ DNA). This viral RNA/DNA damage interferes with viral replication and transcription processes, effectively inhibiting viral propagation. Additionally, ROS can target viral proteins, further disrupting essential viral functions and leading to viral inactivation. Immunomodulation  SiO2 nanoparticles have demonstrated the ability to modulate the immune response. When in contact with immune cells, such as macrophages or dendritic cells, SiO2 nanoparticles can stimulate the release of specific cytokines and chemokines. These signaling molecules activate other immune cells, enhancing the host’s antiviral defense mechanisms. Increased production of antiviral cytokines, such as interferons, can inhibit viral replication and promote the elimination of infected cells. Additionally, SiO2 nanoparticles can enhance the activity of natural killer cells, which are keys in identifying and eliminating virus-infected cells. SiO2 nanoparticles exhibit diverse and promising antiviral mechanisms, including viral attachment inhibition, viral capsid disruption, ROS-mediated RNA/DNA damage, and immunomodulation. These mechanisms collectively contribute to the antiviral activity of SiO2 nanoparticles, making them attractive candidates for biomedical applications, including COVID-19 prevention and treatment. Understanding the intricacies of these antiviral mechanisms is essential for harnessing the full potential of SiO2 nanoparticles in combating viral infections and advancing public health efforts. Further research and development in this area hold great promise for developing effective antiviral strategies and improving global health outcomes.

Reducing the Toxicity of Silica (SiO2) SiO2 is a widely used material in various industrial and medical applications, but its potential toxicity poses significant health concerns (Huang et al., 2022). To minimize its adverse effects on living cells and human health, several strategies can be employed to decrease the toxicity of silica particles.

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

75

Particle Size and Shape Optimization  Studies have shown that smaller silica particles, especially those in the nanoscale range, tend to be more toxic than the larger particles (Chiang et al., 2011). Therefore, controlling the size and shape of silica particles can help reduce their toxicity. By using larger, less respirable particles in industrial applications can limit their potential to be inhaled and cause lung damage. This approach ensures that silica particles are less likely to penetrate deep into the lungs, reducing the risk of respiratory and other related health issues. Surface Modification  Surface modification is a crucial strategy to reduce the toxicity of SiO2 (Mamaeva et al., 2013). The surface properties of silica play a significant role in their interaction with cells.  The modification of the surface of silica particles through coatings or functionalization, can alter their behavior and mitigate potential toxic effects. Mainly, SiO2 NPs with positively charged surfaces have been shown to be more toxic than those with negatively charged surfaces (Huang et al., 2022). Various surface modification techniques can be applied to silica particles, using materials, such as polymers, surfactants, lipids, metal and metal oxides, and biomimetic materials (Duan et al., 2018; Huang et al., 2022; Mahtabani et al., 2020; Wang et al., 2012). For instance, the addition of biocompatible coatings or surfactants can help minimize cellular uptake and decrease the release of toxic substances, making the silica particles safer for biological systems and applications. Surface modification allows for tailoring silica particles’ properties to specific needs while enhancing their biocompatibility and reducing potential health risks. Encapsulation and Containment  Silica particles can be encapsulated or incorporated into matrices or carriers (e.g., Liposomes, Polymeric Nanoparticles, Hydrogels, Micelles, Dendrimers, Mesoporous Silica Nanoparticles, and Protein-based carriers) that prevent direct contact with cells (Yang et al., 2020; Zare et al., 2021). This approach is especially useful in medical applications where silica is used as a drug delivery system. Encapsulation can enhance biocompatibility and reduce unwanted interactions with cells. By encapsulating silica particles within protective carriers, the potential adverse effects of silica on living cells can be minimized, enabling targeted drug delivery and controlled release while shielding the drug cargo and surrounding tissues from potential toxicity. Furthermore, the choice of carriers and matrices can be tailored to specific applications and targeted delivery sites, ensuring optimal therapeutic outcomes and minimal side effects. By employing strategies, such as particle size and shape optimization, surface modification, and encapsulation, researchers and industries can effectively reduce the toxicity of silica particles. These approaches enable the safe use of silica in various applications while minimizing the potential risks to human health. By implementing these methods and continuously advancing research, we can ensure silica’s responsible and beneficial use across diverse fields, including medicine, manufacturing, and beyond.

76

V. Kokkarachedu et al.

Recent Applications SiO2 has unique properties that make it highly versatile for biomedical applications. When interacting with other materials, especially hydroxyapatite (HA), SiO2 can act as a reinforcement agent in HA coatings, enhancing their mechanical properties (Sheykholeslami et al., 2023). The mesoporous structure of SiO2 allows for controlled drug delivery, making it an excellent candidate for biomedical implants. Concerns about SiO2 toxicity, especially in nanoscale particles, exist. However, using mesoporous SiO2 particles in controlled concentrations can mitigate toxicity risks. Biocompatibility studies have been conducted using various cell lines, including lung epithelial cells, skin fibroblasts, and osteoblasts, demonstrating the safety and viability of SiO2/HA composite coatings. Additionally, by combining SiO2 with biocompatible materials, e.g. HA, further enhances the safety profile of composite coatings. Biomedical applications of novel spherical mesoporous SiO2/HA particles in electrodeposited HA coatings include orthopedic and dental implants. These coatings improve tissue regeneration, prevent infections, and offer personalized drug delivery. The innovative SiO2/HA coatings hold promise to revolutionize biomedical engineering and enhance patient care. However, the incorporation of SiO2 into biomedical coatings offers exciting possibilities for enhancing implant performance and patient outcomes. Biocompatibility studies with various cell lines have demonstrated the safety and viability of SiO2/HA composite coatings. With careful consideration of toxicity and biocompatibility, SiO2/HA composite coatings can transform the field of biomedical implants and personalized medicine. Further research and validation are needed to fully harness the potential of these innovative coatings in biomedical applications. Nahrawy et al., reported that “Integrated use of nickel cobalt aluminoferrite/Ni2+ nano-crystallites supported with SiO2 for optomagnetic and biomedical applications” explores the potential of using nickel cobalt aluminoferrite/Ni2+ nano-­ crystallites supported with SiO2 for optomagnetic and biomedical applications (El Nahrawy et al., 2021). This study focuses on the synthesis and characterization of the materials and their potential for use in various applications. This study found that the materials exhibited enhanced magnetic properties, making them useful for optomagnetic applications, such as magnetic resonance imaging (MRI). Additionally, the biocompatibility of SiO2 makes it a good candidate for biomedical applications, such as drug delivery systems. The authors also reported on the antibacterial activity of the materials against four nosocomial pathogens, including Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. The authors suggest that this antibacterial activity could make the materials useful for biomedical applications such as wound healing and infection control. Overall, this study demonstrates the potential of using these materials in various applications that require both magnetic and biocompatible properties. Qiao et al., reported loading SiO2 into polydopamine-functionalized TiO2 nanotubes for potential biomedical applications (Qiao et al., 2019). The study aimed to investigate the interaction between SiO2 and TiO2 as well as the effect of this

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

77

interaction on cell attachment, proliferation, and other cellular behaviors in MC3T3-E1 cells, which are used in bone-related research due to their osteoblastic nature and their relevance in studying the bone formation and regeneration. SiO2 was chosen as a potential drug delivery carrier due to its biocompatibility and ability to be loaded with various drugs. The polydopamine-functionalized TiO2 nanotubes were used as a substrate for SiO2 due to their high surface area and biocompatibility. The study found that the SiO2-loaded nanotubes had improved cell attachment and proliferation compared to the control group. The interaction between SiO2 and TiO2 was found to enhance the cellular behaviors of MC3T3-E1 cells. These results suggest that SiO2-loaded polydopamine-functionalized TiO2 nanotubes have the potential as a substrate for biomedical applications. Another study demonstrated that the sol–gel derived Zn-doped SiO2-­ hydroxypropyl cellulose nanohybrids exhibit biocompatibility with mammalian cells (human embryonic kidney cells; HEK293) and antibacterial activity against taphylococcus aureus and Escherichia coli (Angelova et  al., 2019). The authors suggest that the SiO2 component of the nanohybrids plays a significant role in enhancing the antibacterial activity of the nanohybrids. The SiO2 component provided a high surface area and facilitated the release of Zn2+, which disrupted the bacterial cell membrane integrity and led to bacterial cell death. These findings suggest that the Zn-doped SiO2-hydroxypropyl cellulose nanohybrids have potential biomedical applications in the development of antibacterial agents for wound healing and other medical applications. SiO2 nanoparticles are employed as the stable core in a core-shell structure with carbon and silver (Ag) (Yang et al., 2023). The SiO2 core exhibits excellent adsorption properties, making it an ideal candidate for the encapsulation and removal of organic contaminants in environmental remediation applications. Additionally, the Ag shell enhances the composite’s antibacterial properties, effectively inhibiting bacterial growth and making it a promising antibacterial agent. The combination of SiO2, carbon, and silver in the core-shell structure contributes to the composite’s high stability and multifunctionality, making it a potential solution for both organic contaminants degradation and antibacterial applications. In the study of Ag@SiO2 core-shell nanoparticles (Alimunnisa et al., 2017), the Ag shell demonstrated potent antibacterial properties against two common bacterial strains, Staphylococcus aureus and Escherichia coli, effectively inhibiting bacterial growth. Notably, the zone of inhibition produced by the Ag@SiO2 nanoparticles varied, based on the concentration of the nanoparticles and the specific bacterial strain tested. For Staphylococcus aureus, the highest zone of inhibition (24  mm) was achieved at a concentration of 1000  μg/mL for Ag@SiO2 (0.5  mL of Tetraethoxysilane). For Escherichia coli, the highest zone of inhibition (16  mm) was observed at a concentration of 1000  μg/mL for Ag@SiO2 (0.5  mL of Tetraethoxysilane). These results highlighted the concentration-dependent nature of the antibacterial activity of Ag@SiO2 core-shell nanoparticles. The study’s findings support the notion that these nanoparticles hold great promise for addressing bacterial infections and environmental remediation, making them potential candidates for various antibacterial interventions and environmental cleanup applications.

78

V. Kokkarachedu et al.

Lately, researchers have investigated the potential use of mesoporous SiO2/nano metal oxide composite spheres as antibacterial agents (Hou et al., 2018). The study evaluated the effectiveness of these composite spheres against Staphylococcus aureus in both dark and LED (20 W light-emitting diode) light-illuminated conditions. The researchers incorporated various types of metal oxides, including Ag2O, Cu2O, CeO2, and NiO, into the SiO2 spheres and found that the composite spheres exhibited enhanced antibacterial activity compared to pure SiO2 spheres. The researchers suggested that the antibacterial activity of the composite spheres was due to their ability to generate ROS upon exposure to light (Fig. 1). The study also highlighted the potential cost-effectiveness of these composite spheres for antibacterial applications, as the use of low-cost precursors and simple synthesis methods could make them a cost-effective alternative to traditional antibacterial agents. Overall, this study provided valuable insights into the potential use of mesoporous SiO2/nano metal oxide composite spheres as a cost-effective and efficient antibacterial agent. The sol–gel method was used to synthesize Ag-doped SiO2 nanoparticles with varying concentrations (Munir et al., 2023). The nanoparticles were amorphous in structure, spherical in shape, and had an average size of 10–20 nm. Optical analysis revealed a broad absorption band (238 nm) in the UV–Vis region. The antibacterial activity of the nanomaterials was tested against Escherichia coli, and significant activity was observed at higher concentrations of Ag. The anticancer activity of the nanoparticles was tested against HepG2 (hepatoblastoma) cell line, a human liver cancer cell line, and significant anticancer activity was observed at high concentrations of Ag. Overall, the Ag-doped SiO2 nanoparticles synthesized via the sol–gel method have demonstrated promising antibacterial and anticancer activities and could be used in various biomedical applications. In another study, ceria and silica nanospheres (CeO2@SiO2 NSs) were assembled with a pencil graphite electrode (PGE) for sensing ascorbic acid and its antibacterial properties (Yadav et  al., 2023). The NSs were synthesized by  using a simple sol–gel method, characterized with the use of  various techniques, and assembled with a PGE in order to develop a sensing platform for ascorbic acid. The electrochemical performance of the CeO2@SiO2 NSs/PGE electrode was evaluated by  using cyclic voltammetry and differential pulse voltammetry. The study also demonstrated the antibacterial activity of CeO2@SiO2 NSs against Escherichia coli and Staphylococcus aureus, attributed to the release of ROS from the CeO2 nanoparticles. Recently, eco-nanocomposites were made from chitosan-corn starch-SiO2/Ag by using a simple and eco-friendly method (Abou Hammad et al., 2023). Cationic chitosan and corn starch were used as the matrix, while SiO2 and Ag were used as the reinforcement and antibacterial agents. The results of the study showed that the nanocomposites had good optical properties and were effective in inhibiting the growth of four types of bacteria, including Staphylococcus haemolyticus, Staphylococcus aureus, Klebsiella pneumoniae, and Escherichia coli. The nanocomposites demonstrated their  bioactivity by forming a hydroxyapatite layer on their surfaces, which is a desirable property for biomedical applications. Furthermore,

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

79

Fig. 1  Scheme of antibacterial mechanisms of SiO2-based materials by thermal process (Hou et al., 2018)

the nanocomposites were capable of releasing Ag at concentrations of 1.3, 1.9, and 2.5 moL %, which is important for maintaining their antibacterial properties over time. The study suggests that chitosan-corn starch-SiO2-based doped with Ag eco-­ nanocomposites have great potential for use in various applications, including biomedical and environmental fields, where their antibacterial properties can be utilized to combat harmful microorganisms. The researchers investigated the antibacterial activity of carboxymethyl cellulose (CMC) films treated with Ag@GO decorated SiO2 nanohybrids against Escherichia

80

V. Kokkarachedu et al.

coli, Pseudomonas aeruginosa, and Staphylococcus aureus (Salimi & Nigje, 2022). The SiO2 nanoparticles were used to decorate the Ag@GO nanohybrids and enhance their antibacterial activity. The researchers found that the synergistic effect of Ag@ GO and SiO2 nanoparticles could generate ROS and damage bacterial cell walls, leading to enhanced antibacterial activity. Therefore, the SiO2 nanoparticles helped to enhance the antibacterial activity of the Ag@GO decorated CMC films against the tested bacterial strains. The stabilization of Ag/SiO2 nanoparticles was achieved  with lignin, derived from rice husk for antifungal (Aspergillus flavus) and antibacterial activities (Escherichia coli, Staphylococcus aureus) (Tran et  al., 2023). The nanoparticles were synthesized using a sol–gel method and characterized using various techniques. The study demonstrates that the Ag/SiO2 nanoparticles stabilized with lignin exhibit significant antibacterial and antifungal activities and are biocompatible and non-toxic to human cells. The use of lignin derived from rice husk as a stabilizing agent for Ag/SiO2 nanoparticles can improve their stability, biocompatibility, and antibacterial/antifungal activities, making them a promising candidate for various biomedical applications. To develop antibacterial cement, SiO2 is also used with other materials. The production of antibacterial cement composites containing ZnO/lignin and ZnO-SiO2/ lignin hybrid admixtures was developed (Klapiszewska et al., 2021). The nanomaterials exhibited significant antibacterial activity toward Escherichia coli and Staphylococcus aureus, attributed to the release of zinc ions from the nanoparticles. The addition of ZnO/lignin and ZnO-SiO2/lignin hybrid admixtures also improved the mechanical properties of the cement matrix. The results suggest that the hybrid nanomaterials have potential for various construction applications. In this investigation, SiO2 was used as a coating material for nanoparticles to enhance their stability and biocompatibility. The silica coating also provided a surface for functionalization, allowing for the attachment of various biomolecules or targeting ligands to the nanoparticles. In addition to its usage as a coating material, SiO2 was also used as a reinforcing agent in composite materials, including cement composites. The addition of SiO2 to cement composites can improve their mechanical properties, such as compressive strength and flexural strength. Overall, the unique properties of SiO2 make it a versatile material with various applications in nanotechnology, biomedicine, and materials science. The antibacterial PVDF/SiO2/Ag composite nanofiber membrane was prepared by  using an electrospinning technique, where a blend of polyvinylidene fluoride (PVDF), SiO2, and Ag were electrospun to form a nanofiber membrane (Wu et al., 2023). The membrane was then, subjected to heat treatment to improve its mechanical and thermal stability. The addition of SiO2 and Ag nanoparticles to the PVDF matrix enhances the antibacterial properties of the membrane, making it effective against a wide range of bacteria. The SiO2 particles also improved the membrane’s mechanical strength and thermal stability, while the Ag nanoparticles provided excellent antibacterial activity. The membrane’s filtration performance was  also improved due to the unique properties of the nanofibers. The small diameter of the nanofibers allowed for a high surface area-to-volume ratio, which enhanced the

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

81

filtration efficiency. The nanofibers also exhibited a high porosity and small pore size, which helped to trap bacteria and other contaminants. Overall, the antibacterial PVDF/SiO2/Ag composite nanofiber membrane had excellent antibacterial properties, mechanical strength, thermal stability, and filtration performance, making it a promising material for various applications such as water treatment, air filtration, and biomedical devices. Silica-coated bismuth (Bi@SiO2) nanoparticles were  synthesized by  using pulsed laser ablation in liquid, a technique that involves the use of a high-energy laser to ablade a solid target in a liquid medium (Hassan et al., 2023). The abladed material forms nanoparticles in the liquid, which are then coated with silica to enhance their stability and biocompatibility. These nanoparticles were  characterized and found to have antibacterial activity (against Escherichia coli and Staphylococcus aureus). The silica coating provided stability to the bismuth nanoparticles and prevented them from agglomerating. The antibacterial activity of these nanoparticles was attributed to their ability to generate ROS upon exposure to light. In addition, the diameter of the inhibition zones increased with the silica shell thickness and the nanoparticles’ concentration. This suggests that the antibacterial activity of SiO2 particles can be tuned by controlling the thickness of the Si shell and the concentration of nanoparticles, making them a promising candidate for various biomedical applications. The development of  new materials for biomedical applications is crucial, and recent studies have shown promising results with magnetic nanoparticles (Jabbar & Ammar, 2019). Magnetic properties, superparamagnetism, and drug-carrying ability make them practical for use in antibacterial and anticancer drug delivery applications and wound-healing applications. Easy separation and recovery after use further enhance their practicality. Recently, magnetic and antibacterial nanoparticles were developed for biomedical applications by  using Fe3O4, SiO2, and Ag nanoparticles synthesized through seed-mediated growth methods (Romdoni et  al., 2023). The nanoparticles were found to have good crystallinity and a core-shell structure, with superparamagnetic properties and surface plasmon resonance (SPR) absorption at ⁓370  nm. These nanoparticles were also used to carry drugs, and epirubicin (EPI)-loaded Fe3O4@ SiO2-Ag nanoparticles were found to have cytotoxic properties against HeLa cells, indicating their potential use as an anticancer drug carrier. In addition, the antibacterial study demonstrated that the nanoparticles exhibited potential inhibition activity toward E. coli and S. aureus, with an inhibition zone of around 8–10 mm. Overall, the results suggest that magnetic nanoparticles have significant potential for use as both an antibacterial agent and an anticancer drug carrier in biomedical applications. The  production of Ag nanoparticles, that anchored  the flower-like magnetic Fe3O4@SiO2@MnO2 hybrids and their potential applications in antibacterial and wound-healing activities were investigated in this paper (Jia et al., 2021). The results showed that the hybrids exhibited excellent antibacterial activity toward gram-­ negative and positive bacteria, which was attributed to the synergistic effects of the silver nanoparticles and the magnetic Fe3O4@SiO2@MnO2 hybrids. The silica component of the hybrids also contributed to their antibacterial properties, which could

82

V. Kokkarachedu et al.

potentially be utilized in biomedical applications. In-vitro experimental results of hybrids demonstrated that the Minimum Inhibitory Concentration (MIC) against Escherichia coli and Staphylococcus aureus were 60 and 100 μg mL−1, respectively. The magnetic hybrids played a crucial role in anchoring the Ag nanoparticles and allowed for easy separation and recovery of the nanoparticles after use. Additionally, in vitro studies demonstrated that the hybrids had significant wound-healing activity, which was attributed to their ability to promote cell migration and proliferation. The potential applications of these hybrids in wound healing are promising due to their excellent antibacterial and wound-healing properties. Overall, they provide valuable insights into the development of new materials for wound-healing applications, and the results suggest that these Ag nanoparticles anchored flower-like magnetic hybrids have significant potential for use in biomedical applications. The magnetic properties of the hybrids also make them a practical choice for wound dressing applications. Nozari et al., discuss the development of a stable (ZnO/SiO2) nano-coating on polyester for anti-bacterial, self-cleaning, and flame retardant applications (Nozari et al., 2021). The nanoparticles were loaded onto PET fabric at 90 °C under alkali conditions by in-situ synthesis. The results showed that the coating exhibited excellent anti-bacterial properties against Escherichia coli bacteria. Additionally, the coating demonstrated self-cleaning properties under UV irradiation, which is attributed to the photocatalytic activity of the ZnO nanoparticles. The SiO2 nanoparticles in the coating also contributed to its stability and adhesion to the polyester fabric. Overall, the results suggest that the nano coating has significant potential for use in various applications, such as medical textiles, outdoor textiles, and home textiles. Researchers have developed SiO2-based materials for air and water filtration in response to the growing need to prevent the spread of airborne and waterborne diseases (Yu et al., 2023; Zhu et al., 2018). Lately, composite membranes are made of poly(vinyl alcohol) and poly(acrylic acid), which are environmentally friendly materials (Zhu et al., 2018). The electrospinning and (UV reduction and thermal) crosslinking methods used to create the membranes result in a highly porous structure, which makes them effective for air filtration. To further enhance the antibacterial properties of the composite membranes, the researchers incorporated SiO2-Ag particles. These particles are made of Ag nanoparticles embedded in superhydrophobic SiO2 and have been shown to have strong antibacterial properties. The SiO2-Ag nanomaterials in the composite membranes act as a barrier to bacterial growth, preventing bacteria from passing through the membrane and into the air. However, these composite membranes create a compelling and environmentally friendly air filtration material that can help prevent the spread of airborne diseases. The incorporation of SiO2-Ag particles enhances the antibacterial properties of the membranes, making them even more effective at filtering bacteria from the air. Another important application of SiO2-based nanofibrous aerogels, is in water disinfection. The aerogel is composed of SiO2 and Ag nanoparticles, which together, form a conductive (Yu et al., 2023) network that allows for efficient electron transfer during the disinfection process. Additionally, the spider-web-inspired structure of the aerogel gives it superelastic properties, allowing it to be stretched and

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

83

compressed without losing its shape or functionality. One of the key advantages of SiO2-­based nanofibrous aerogels is their antibacterial properties. The surface of SiO2 nanofibers can be functionalized with antibacterial agents, such as chitosan or silver nanoparticles, which can help kill or inhibit the growth of bacteria. This makes the aerogel material particularly useful for water disinfection applications, as it can help to ensure that the treated water is safe for consumption or other uses. Yu et al. described the use of electroporation as a disinfection method (Yu et al., 2023). Electroporation is a process in which an electric field is applied to a solution containing bacteria, causing pores to form in the bacterial cell membranes and ultimately leading to cell death. The conductive network within the SiO2/Ag nanofibrous aerogel material allows for efficient electron transfer during electroporation, making this disinfection method even more effective. Overall, the Spider-WebInspired SiO2/Ag Nanofibrous Aerogels with Superelastic and Conductive Networks for Electroporation Water Disinfection paper highlights the many useful properties of SiO2-based nanofibrous aerogels, including their antibacterial properties and ability to enhance the effectiveness of electroporation as a water disinfection method. The novel photosensitization process developed in this research utilizes a C60 fullerene covalently attached to a functionalized SiO2-coated stainless-steel mesh to remotely inactivate bacteria and viruses, including the Staphylococcus aureus and MS2 bacteriophage (emesvirus zinderi) (Kim et al., 2020). The researchers aimed to explore a new approach that could remotely inactivate these pathogens without the need for direct contact or the use of harmful chemicals. The study utilized a C60 fullerene covalently attached to a functionalized SiO2-coated stainless-steel mesh to produce singlet oxygen upon exposure to light. The process was demonstrated to be highly effective in remotely inactivating bacteria and viruses. However, the SiO2 coating was used to modify the surface of the stainless-steel mesh to enhance its properties and provide a stable platform for the attachment of the C60 fullerene. In addition to its use in the photosensitization process, SiO2 was also explored for its interactions with other materials. The study found that SiO2 can interact with metals to improve their corrosion resistance or with polymers to enhance their mechanical strength. These interactions can be tailored to achieve specific properties and applications, making SiO2 versatile for developing new materials and technologies. Overall, this approach represents a promising strategy for developing new antimicrobial surfaces with potential applications in a wide range of settings.

Antiviral Applications Silica-based nanoparticles have shown promising antiviral properties toward many viruses, including herpes simplex virus, human immunodeficiency virus, and influenza A virus (Tng & Low, 2023). They can also be used to deliver antiviral drugs directly to infected cells. However, further research is required to fully understand

84

V. Kokkarachedu et al.

the mechanisms underlying the antiviral activity of silica-based nanoparticles as well as their potential toxicity and immunogenicity. Silica-based nanosystems are promising in combating antibiotic-resistant bacteria and pathogenic viruses (Iravani, 2022). They possess antibacterial properties, enable controlled drug delivery, inhibit viruses, and have low toxicity. SiO2 can be incorporated into coatings or fabrics to provide antiviral activity and can be functionalized with other molecules to enhance its effectiveness against specific viruses (Tsutsumi-Arai et  al., 2022). SiO2-based antiviral treatments have the potential for a variety of applications, including in the production of personal protective equipment. Silica has recently been used to develop innovative air filters for control viruses. A new type of air filter coating utilizes a photobiocidal-triboelectric nanolayer made of photosensitizer and silica–alumina (Jeong et al., 2022). This technology shows potential to be applied to mask filters as well. The photobiocidal-triboelectric nanolayer coating efficiently eliminates bacteria and viruses, with a photobiocidal efficiency of up to 99.9%. The photosensitizer is activated by visible light, producing ROS that effectively kills microorganisms. The silica–alumina matrix enhances the coating’s durability and stability, making it reusable. Overall, this technology has potential applications in air filtration systems and mask filters, particularly in public spaces where air quality is a concern. A  recent study described a method for rapidly determining antiviral drugs in yellow catfish by using graphene/silica nanospheres (G/KCC-1)-based pipette tip solid-phase extraction with ultra-performance liquid chromatography–tandem mass spectrometry (Shen et  al., 2022). The SiO2 component of the G/KCC-1 material plays an important role in the solid-phase extraction process. Silica has a high surface area and strong adsorption capacity, which allows it to effectively extract antiviral drugs from the fish samples. The ultra-performance liquid chromatography– tandem mass spectrometry provides high sensitivity and its selectivity for the detection and quantification of the antiviral drugs. The combination of graphene and silica in the G/KCC-1 material provides additional benefits, such as improved mechanical strength and thermal stability. Overall, this method shows promise in ensuring the safety and quality of fish products for human consumption and demonstrates the usefulness of SiO2 in solid-phase extraction for the detection and quantification of antiviral drugs in fish samples.

SiO2-Based Materials for Coronavirus Disease 2019 (COVID-19) Applications The development of a spike protein-based fluorescence lateral flow assay for the simultaneous detection of SARS-CoV-2-specific immunoglobulin-M (IgM) and immunoglobulin-G (IgG) antibodies represents a significant advancement in COVID-19 diagnostics (Sun et al., 2020). This assay aims to provide a rapid, reliable, and sensitive process for identifying the presence of both IgM and IgG

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

85

antibodies, which are crucial indicators of the immune response to SARS-CoV-2 infection. The spike protein of SARS-CoV-2 plays a vital role in the virus’s entry into host cells and serves as the primary target of the immune response. By utilizing the spike protein as the antigen in this assay, it becomes possible to achieve specific and sensitive detection of SARS-CoV-2 antibodies. The integration of fluorescence detection within the lateral flow assay format combines the advantages of rapid lateral flow technology with the enhanced sensitivity and quantitative capabilities provided by fluorescence-based measurements. In the development of this assay, SiO2 plays a critical role as the substrate or carrier material for immobilizing the spike protein antigen. SiO2 possesses unique properties, including a high surface area, stability, and biocompatibility, making it an excellent choice for immobilizing biomolecules. The utilization of SiO2-based substrates provides solid support for the attachment of the spike protein, ensuring its stability and preserving its antigenic properties during the assay. However, effective COVID-19 detection strips have been developed from the silica-core at dual quantum dot shell (Wang et al., 2020). In order to improve the SiO2 applicability in medical applications, it can be functionalized with suitable chemistry to create a stable and robust surface for immobilizing the spike protein antigen. This functionalization process often involves modifying the surface of SiO2 to introduce amino groups, allowing for covalent attachment of the spike protein antigen (Fig. 2) (Wang et al., 2021). Through this immobilization process, the spike protein retains its structural integrity and antigenic activity, enabling accurate detection of SARS-CoV-2 specific IgM and IgG antibodies (Fig. 2). Moreover, the SiO2 substrate plays a crucial role in the assembly of the lateral flow assay components. It serves as the backbone for the construction of the lateral flow strip, which typically consists of different layers such as the sample pad, conjugate pad, nitrocellulose membrane, and absorbent pad. The SiO2 substrate provides structural support and facilitates the flow of the sample and reagents through the lateral flow strip, ensuring efficient and accurate analyte detection. The high surface area and porosity of SiO2 can be harnessed to further enhance the performance of the lateral flow assay. By modifying the surface properties of SiO2, such as pore size and surface chemistry, it becomes possible to optimize the flow characteristics and binding efficiency of the lateral flow strip (Wang et  al., 2021). This optimization leads to improved sensitivity, specificity, and overall performance of the assay, enabling the reliable detection of SARS-CoV-2 specific IgM and IgG antibodies. Beyond the context of this specific lateral flow assay, SiO2based materials have found extensive utilization in various aspects of COVID-19 diagnostics. For instance, SiO2 nanoparticles have been employed in the development of biosensors, viral RNA extraction methods, and vaccine delivery systems. The unique properties of SiO2, including stability, biocompatibility, and ease of functionalization, have made SiO2 nanoparticles invaluable in enhancing the sensitivity and specificity of diagnostic assays and facilitating efficient vaccine delivery. In summary, SiO2 plays a vital and multifaceted role in the development of spike protein-based fluorescence lateral flow assays for the simultaneous detection of SARS-CoV-2 specific IgM and IgG antibodies. By serving as the substrate for

86

V. Kokkarachedu et al.

Fig. 2  Schematic diagram of the (a) preparation of SiO2@DQD with a dual QD-shell, and (b) principle of the SiO2@DQD-based LFA stip for SARS-CoV-2-IgM-IgG rapid and simultaneous detection (Wang et al., 2021)

antigen immobilization, SiO2 provides stability and preserves the antigenic properties of the spike protein. Additionally, SiO2-based materials contribute to the assembly of the lateral flow strip, enhancing the overall performance of the assay. The unique properties and versatility of SiO2 make it a valuable component in various aspects of COVID-19 diagnostics and research. SiO2 is used as a component of the sensing probe for the determination of anti-­ COVID-­19 Remdesivir in pharmaceutical dosage forms and biological fluids (Rizk et al., 2022). SiO2 is used as a support material for the gold nanoparticles that are functionalized with Remdesivir-specific aptamer sequences. The SiO2 support enhances the stability of the gold nanoparticles and helps to prevent agglomeration, which is important for maintaining the sensitivity and selectivity of the sensing probe. Additionally, SiO2 has a high surface area and can be easily modified by a number of functional groups, making it a versatile support material for a range of sensing applications. The use of SiO2 in this sensing probe is important because it allows for the specific detection of Remdesivir, an important antiviral drug used in the treatment of COVID-19. The sensing probe can be used to detect Remdesivir in both pharmaceutical dosage forms and biological fluids, which is important for

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

87

monitoring drug levels in patients and ensuring proper dosing. The development of this sensing probe represents a main step forward in the fight against COVID-19, as it provides a sensitive and selective tool for detecting Remdesivir in a range of settings. SiO2 has been used for the development of core/shell nanoparticles. It is mainly used as a core material for the SiO2@Au core-satellite nanoparticles that are used in the lateral flow immunosensors to detect SARS-CoV-2 nucleocapsid protein (Hong et al., 2022). SiO2 is used as a core material because it has a high surface area and can be easily functionalized with various biomolecules, making it an ideal material for use in biosensors. In the SiO2@Au core-satellite nanoparticles, the SiO2 core is coated by a layer of Au nanoparticles that act as satellites. The Au nanoparticles are functionalized with SARS-CoV-2 nucleocapsid protein-specific antibodies, which allows for the selective detection of the protein in patient samples. The SiO2 core acts as a spacer between the Au nanoparticles, which helps to modulate the absorption of light by the nanoparticles. This modulation of light absorption is important for enhancing the sensitivity of the lateral flow immunosensors, which allows for the detection of SARS-CoV-2 nucleocapsid protein at very low concentrations. Overall, SiO2 is an important component of the core-satellite nanoparticles because it allows for the functionalization of the nanoparticles with biomolecules and helps to modulate light absorption, which enhances the sensitivity of the lateral flow immunosensors. The development of this biosensor represents a significant step forward in the fight toward COVID-19, as it provides a sensitive and selective tool for detecting SARS-CoV-2 nucleocapsid protein in patient samples. The SiO2 and Ag materials are used to control the virus. SiO2 plays a significant role in the development of the SiO2-Ag composite as a biocidal material against SARS-CoV-2. The use of SiO2 in the composite enhances its mechanical stability and biocidal properties, which represents an important achievement in the fight against COVID-19. The study by Oliveira et al. uses experimental and theoretical methods to investigate the biocidal activity of the SiO2-Ag composite (de Oliveira et al., 2023). The results of the study show that the SiO2-Ag composite has intrinsic biocidal activity against SARS-CoV-2, which is due to the release of Ag+ from the composite material. The Ag+ are highly reactive and can bind to various biomolecules on the surface of the virus, including proteins and nucleic acids. This interaction disrupts the structure and function of the virus, which can prevent it from infecting host cells. The silver ions can also cause damage to the viral envelope, which can further inhibit its ability to infect host cells. However, the SiO2 component of the composite is important because it provides mechanical stability to the material and enhances its durability. The SiO2 also helps to prevent agglomeration of the Ag nanoparticles, which can improve the biocidal properties of the composite. The SiO2 component of the composite is important because it provides mechanical stability to the material and enhances its durability. The SiO2 also helps to prevent agglomeration of the silver nanoparticles, which can improve the biocidal properties of the composite. Overall, the development of the SiO2-Ag composite represents an important achievement in the fight against COVID-19, as it provides a biocidal material that can help prevent the spread of SARS-CoV-2. The use of

88

V. Kokkarachedu et al.

SiO2 in the composite enhances its mechanical stability and biocidal properties, which highlights the importance of nanotechnology in developing innovative solutions to combat infectious diseases. The development of a SiO2-Ag composite material for the rapid elimination of SARS-CoV-2, the virus that causes COVID-19. Generally, both SiO2 and Ag play important roles in the virucidal activity of the composite material. SiO2 acts as a carrier for Ag nanoparticles, which have been shown to have potent antiviral activity against a range of viruses. The SiO2 matrix helps to stabilize the Ag nanoparticles and prevent aggregation, ensuring that they remain effective over time. Additionally, the SiO2-Ag composite material can be functionalized with other antiviral agents, such as quaternary ammonium compounds, to enhance its activity against SARS-­ CoV-­2. Marcelo Assis et al. describe how the SiO2-Ag composite material interacts with SARS-CoV-2 to rapidly eliminate the virus (Assis et  al., 2021a). The Ag nanoparticles in the composite material can disrupt the viral envelope, preventing the virus from entering host cells and inhibiting viral replication. Additionally, the SiO2-Ag composite material can generate ROS when exposed to light, which can damage viral RNA and further inhibit viral replication. Overall, SiO2 and Ag play important roles in the virucidal activity of the SiO2-Ag composite material described in this paper. SiO2 acts as a carrier for Ag nanoparticles, while Ag disrupts the viral envelope and generates ROS to damage viral RNA. Together, these properties make the SiO2-Ag composite material a promising candidate for the rapid elimination of SARS-CoV-2 and other viruses. The development of biocidal materials, such as the polyvinyl chloride (PVC)SiO2-Ag composite, is important because it can prevent the spread of infectious diseases, including SARS-CoV-2 (Assis et al., 2021b). In the PVC-SiO2-Ag composite material, SiO2 acts as a mechanical support for the silver (Ag) nanoparticles. Ag nanoparticles are known for their potent antimicrobial properties, but they can be unstable and easily agglomerate, which can reduce their effectiveness. By incorporating SiO2 into the composite, the Ag nanoparticles are more evenly distributed and stabilized, which enhances their biocidal properties. Additionally, SiO2 itself has mechanical properties that improve the overall durability and strength of the composite material, making it a potent biocide and anti-SARS-CoV-2 material. Additionally, these materials have potential applications in a variety of settings, including hospitals, public transportation, and other high-traffic areas where the risk of infection is high. Overall, the development of biocidal materials like the PVCSiO2-Ag composite represents an important step forward in the fight against infectious diseases.

Future Acceptance As research on SiO2 nanoparticles advances, a number of factors will play a significant role in determining their future acceptance as antimicrobial agents for combating bacterial and viral infections, including COVID-19. One of the primary concerns

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

89

in the widespread adoption of SiO2 nanoparticles is their potential toxicity to human cells and the environment. Extensive studies will be required to assess their biocompatibility, potential long-term effects, and their impact on various organs and tissues. Researchers will need to develop nanoparticles with reduced toxicity profiles and ensure appropriate dosages that do not pose harm to the human body. Further investigation will be needed to understand the significant mechanisms by which SiO2 nanoparticles exert their antimicrobial effects. Studying their interactions with bacterial and viral cells in more detail will help optimize their design and tailor their properties for maximum efficacy against specific pathogens, including drug-­ resistant strains. Developing SiO2 nanoparticles that can specifically target infectious agents while sparing healthy cells will be crucial. Targeted delivery systems can enhance the efficiency of treatment, minimize side effects, and improve overall therapeutic outcomes. Additionally, the stability and shelf-life of SiO2 nanoparticles will be critical factors in their practical use. Ensuring that these nanoparticles can maintain their integrity and functionality over time is essential for their commercial viability and large-scale production. Obtaining regulatory approval from health authorities is a vital step in accepting SiO2 nanoparticles as a mainstream antimicrobial solution. Standardizing manufacturing processes and quality control measures will be necessary to ensure consistency and safety in their use. However, understanding the environmental impact of SiO2 nanoparticles is essential. Researchers and manufacturers should take measures to minimize any potential adverse effects on ecosystems and the environment during production, use, and disposal. Overall, SiO2-based nanoparticles are promising as potential antimicrobial agents against bacterial and viral infections, including COVID-19. However, to gain widespread acceptance and application, it will be imperative to address concerns related to safety, toxicity, targeted delivery, stability, and environmental impact. Rigorous research, responsible innovation, and adherence to regulatory guidelines are essential to unlock the full potential of SiO2 nanoparticles as a safe and effective tool in the fight against infectious diseases.

Conclusion In conclusion, SiO2 nanoparticles show great promise as potential antimicrobial agents for combating bacterial and viral infections, particularly in the context of COVID-19 prevention and treatment. Their unique physicochemical properties offer opportunities for novel therapeutic approaches. However, to ensure their widespread acceptance and safe implementation, further research is required to address the concerns that are related to toxicity and safety. Striking a balance between efficacy and safety will be crucial for their successful integration into clinical practice. As the field of SiO2 nanoparticle research advances, it can be anticipated that more insights into their applications will be available, fostering innovative strategies in the battle against infectious diseases.

90

V. Kokkarachedu et al.

Acknowledgments  KVP acknowledges Fondecyt Regular Project No. 1211118, ANID, and FIT, USS, Chile.

References Abou Hammad, A. B., Al-esnawy, A. A., Mansour, A. M., & El Nahrawy, A. M. (2023). Synthesis and characterization of chitosan-corn starch-SiO2/silver eco-nanocomposites: Exploring optoelectronic and antibacterial potential. International Journal of Biological Macromolecules, 249, 126077. https://doi.org/10.1016/j.ijbiomac.2023.126077 Agnihothram, S. S., Vermudez, S. A., Mullis, L., Townsend, T. A., Manjanatha, M. G., & Azevedo, M.  P. (2016). Silicon dioxide impedes antiviral response and causes genotoxic insult during calicivirus replication. Journal of Nanoscience and Nanotechnology, 16(7), 7720–7730. https://doi.org/10.1166/jnn.2016.12828 Alimunnisa, J., Ravichandran, K., & Meena, K. S. (2017). Synthesis and characterization of Ag@ SiO2 core-shell nanoparticles for antibacterial and environmental applications. Journal of Molecular Liquids, 231, 281–287. https://doi.org/10.1016/j.molliq.2017.01.103 Angelova, T., Rangelova, N., Georgieva, N., Nemska, V., Stoyanova, T., Uzunova, V., Aleksandrov, L., & Tzoneva, R. (2019). Study of potential biomedical application of sol-gel derived Zn-doped SiO2-hydroxypropyl cellulose nanohybrids. Materials Science and Engineering: C, 100, 608–615. https://doi.org/10.1016/j.msec.2019.03.018 Assis, M., Simoes, L. G. P., Tremiliosi, G. C., Coelho, D., Minozzi, D. T., Santos, R. I., Vilela, D. C. B., Santos, J. R. D., Ribeiro, L. K., Rosa, I. L. V., Mascaro, L. H., Andrés, J., & Longo, E. (2021a). Sio2-ag composite as a highly virucidal material: A roadmap that rapidly eliminates sars-cov-2. Nanomaterials, 11(3), 1–19. https://doi.org/10.3390/nano11030638 Assis, M., Simoes, L. G. P., Tremiliosi, G. C., Ribeiro, L. K., Coelho, D., Minozzi, D. T., Santos, R. I., Vilela, D. C. B., Mascaro, L. H., Andrés, J., & Longo, E. (2021b). PVC-SiO2-Ag composite as a powerful biocide and anti-SARS-CoV-2 material. Journal of Polymer Research, 28(9), 361. https://doi.org/10.1007/s10965-­021-­02729-­1 Bae, J.-H., Cha, J.-M., & Ryu, B.-K. (2019). Production of Cu@SiO2 core–shell nanoparticles with antibacterial properties. Journal of Nanoscience and Nanotechnology, 19(3), 1690–1694. https://doi.org/10.1166/jnn.2019.16152 Bhuiyan, M. A. R., Wang, L., Shanks, R. A., Ara, Z. A., & Saha, T. (2020). Electrospun polyacrylonitrile–silica aerogel coating on viscose nonwoven fabric for versatile protection and thermal comfort. Cellulose, 27(17), 10501–10517. https://doi.org/10.1007/s10570-­020-­03489-­9 Borm, P.  J. A., Fowler, P., & Kirkland, D. (2018). An updated review of the genotoxicity of respirable crystalline silica. Particle and Fibre Toxicology, 15(1), 23. https://doi.org/10.1186/ s12989-­018-­0259-­z Chiang, Y.-D., Lian, H.-Y., Leo, S.-Y., Wang, S.-G., Yamauchi, Y., & Wu, K.  C.-W. (2011). Controlling particle size and structural properties of mesoporous silica nanoparticles using the Taguchi method. The Journal of Physical Chemistry C, 115(27), 13158–13165. https://doi. org/10.1021/jp201017e de Oliveira, M. C., Assis, M., Simões, L. G. P., Minozzi, D. T., Ribeiro, R. A. P., Andrés, J., & Longo, E. (2023). Unraveling the intrinsic biocidal activity of the SiO2 –Ag composite against SARS-CoV-2: A joint experimental and theoretical study. ACS Applied Materials & Interfaces, 15(5), 6548–6560. https://doi.org/10.1021/acsami.2c21011 Duan, J., Liang, S., Feng, L., Yu, Y., & Sun, Z. (2018). Silica nanoparticles trigger hepatic lipid-metabolism disorder in vivo and in vitro. International Journal of Nanomedicine, 13, 7303–7318. https://doi.org/10.2147/IJN.S185348 El Nahrawy, A. M., Hemdan, B. A., Mansour, A. M., Elzwawy, A., & Abou Hammad, A. B. (2021). Integrated use of nickel cobalt aluminoferrite/Ni2+ nano-crystallites supported with SiO2 for

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

91

optomagnetic and biomedical applications. Materials Science and Engineering: B, 274, 115491. https://doi.org/10.1016/j.mseb.2021.115491 Fonseca, S., Cayer, M.-P., Ahmmed, K. M. T., Khadem-Mohtaram, N., Charette, S. J., & Brouard, D. (2022). Characterization of the antibacterial activity of an SiO2 nanoparticular coating to prevent bacterial contamination in blood products. Antibiotics, 11(1), 107. https://doi.org/10.3390/ antibiotics11010107 Fu, Q., Liu, Q., Li, L., Li, X., Gu, H., Sheng, B., & Yang, B. (2020). Study on microstructure, microhardness, bioactivity, and biocompatibility of La2 O3 -containing bioceramic coating doping SiO2 fabricated by laser cladding. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 108(5), 2099–2107. https://doi.org/10.1002/jbm.b.34548 Geyao, L., Yang, D., Wanglin, C., & Chengyong, W. (2020). Development and application of physical vapor deposited coatings for medical devices: A review. Procedia CIRP, 89, 250–262. https://doi.org/10.1016/J.PROCIR.2020.05.149 Hassan, S. S., Hubeatir, K. A., & Al-Haddad, R. M. S. (2023). Characterization and antibacterial activity of silica-coated bismuth (Bi@SiO2) nanoparticles synthesized by pulsed laser ablation in liquid. Optik, 273, 170453. https://doi.org/10.1016/j.ijleo.2022.170453 Heldt, C. L., Zahid, A., Vijayaragavan, K. S., & Mi, X. (2017). Experimental and computational surface hydrophobicity analysis of a non-enveloped virus and proteins. Colloids and Surfaces B: Biointerfaces, 153, 77–84. https://doi.org/10.1016/J.COLSURFB.2017.02.011 Hetrick, E.  M., Shin, J.  H., Paul, H.  S., & Schoenfisch, M.  H. (2009). Anti-biofilm efficacy of nitric oxide-releasing silica nanoparticles. Biomaterials, 30(14), 2782–2789. https://doi. org/10.1016/J.BIOMATERIALS.2009.01.052 Hirao, R., Shigetoh, K., Inagaki, S., & Ishida, N. (2023). Virus inactivation based on optimal surfactant reservoir of mesoporous silica. ACS Applied Bio Materials, 6(3), 1032–1040. https:// doi.org/10.1021/acsabm.2c00901 Hong, D., Jo, E.-J., Jung, C., & Kim, M.-G. (2022). Absorption-modulated SiO2 @Au core–satellite nanoparticles for highly sensitive detection of SARS-CoV-2 nucleocapsid protein in lateral flow immunosensors. ACS Applied Materials & Interfaces, 14(40), 45189–45200. https://doi. org/10.1021/acsami.2c13303 Hou, Y.-X., Abdullah, H., Kuo, D.-H., Leu, S.-J., Gultom, N. S., & Su, C.-H. (2018). A comparison study of SiO2/nano metal oxide composite sphere for antibacterial application. Composites Part B: Engineering, 133, 166–176. https://doi.org/10.1016/j.compositesb.2017.09.021 Huang, Y., Li, P., Zhao, R., Zhao, L., Liu, J., Peng, S., Fu, X., Wang, X., Luo, R., Wang, R., & Zhang, Z. (2022). Silica nanoparticles: Biomedical applications and toxicity. Biomedicine & Pharmacotherapy, 151, 113053. https://doi.org/10.1016/J.BIOPHA.2022.113053 Iravani, S. (2022). Silica-based nanosystems against antibiotic-resistant bacteria and pathogenic viruses. Critical Reviews in Microbiology, 1–13. https://doi.org/10.108 0/1040841X.2022.2108309 Jabbar, T. A., & Ammar, S. H. (2019). Core/shell phosphomolybdic acid-supported magnetic silica nanocomposite (Ni@SiO2-PMo): Synthesis, characterization and its application as a recyclable antibacterial agent. Colloid and Interface Science Communications, 33, 100214. https://doi. org/10.1016/j.colcom.2019.100214 Jaganathan, H., & Godin, B. (2012). Biocompatibility assessment of Si-based nano- and micro-­ particles. Advanced Drug Delivery Reviews, 64(15), 1800–1819. https://doi.org/10.1016/j. addr.2012.05.008 Jeong, S. B., Lee, D. U., Lee, B. J., Heo, K. J., Kim, D. W., Hwang, G. B., MacRobert, A. J., Shin, J. H., Ko, H. S., Park, S. K., Oh, Y. S., Kim, S. J., Lee, D. Y., Lee, S.-B., Park, I., Kim, S. B., Han, B., Jung, J. H., & Choi, D. Y. (2022). Photobiocidal-triboelectric nanolayer coating of photosensitizer/silica-alumina for reusable and visible-light-driven antibacterial/antiviral air filters. Chemical Engineering Journal, 440, 135830. https://doi.org/10.1016/j.cej.2022.135830 Jia, H., Hou, W., Wei, L., Xu, B., & Liu, X. (2008). The structures and antibacterial properties of nano-SiO2 supported silver/zinc–silver materials. Dental Materials, 24(2), 244–249. https:// doi.org/10.1016/J.DENTAL.2007.04.015

92

V. Kokkarachedu et al.

Jia, H., Zhang, X., Zeng, X., Cai, R., Wang, Z., Yuan, Y., & Yue, T. (2021). Construction of silver nanoparticles anchored flower-like magnetic Fe3O4@SiO2@MnO2 hybrids with antibacterial and wound healing activity. Applied Surface Science, 567, 150797. https://doi.org/10.1016/j. apsusc.2021.150797 Joe, Y.  H., Woo, K., & Hwang, J. (2014). Fabrication of an anti-viral air filter with SiO2–Ag nanoparticles and performance evaluation in a continuous airflow condition. Journal of Hazardous Materials, 280, 356–363. https://doi.org/10.1016/J.JHAZMAT.2014.08.013 Jurkić, L. M., Cepanec, I., Pavelić, S. K., & Pavelić, K. (2013). Biological and therapeutic effects of ortho-silicic acid and some ortho-silicic acid-releasing compounds: New perspectives for therapy. Nutrition and Metabolism, 10(1). https://doi.org/10.1186/1743-­7075-­10-­2 Karthikeyan, C., Varaprasad, K., Venugopal, S.  K., Shakila, S., Venkatraman, B.  R., & Sadiku, R. (2021). Biocidal (bacterial and cancer cells) activities of chitosan/CuO nanomaterial, synthesized via a green process. Carbohydrate Polymers, 259, 117762. https://doi.org/10.1016/J. CARBPOL.2021.117762 Khannyra, S., Luna, M., Gil, M. L. A., Addou, M., & Mosquera, M. J. (2022). Self-cleaning durability assessment of TiO2/SiO2 photocatalysts coated concrete: Effect of indoor and outdoor conditions on the photocatalytic activity. Building and Environment, 211, 108743. https://doi. org/10.1016/J.BUILDENV.2021.108743 Kim, J., Lee, H., Lee, J.-Y., Park, K.-H., Kim, W., Lee, J. H., Kang, H.-J., Hong, S. W., Park, H.-J., Lee, S., Lee, J.-H., Park, H.-D., Kim, J. Y., Jeong, Y. W., & Lee, J. (2020). Photosensitized production of singlet oxygen via C60 fullerene covalently attached to functionalized silica-­ coated stainless-steel mesh: Remote bacterial and viral inactivation. Applied Catalysis B: Environmental, 270, 118862. https://doi.org/10.1016/j.apcatb.2020.118862 Klapiszewska, I., Parus, A., Ławniczak, Ł., Jesionowski, T., Klapiszewski, Ł., & Ślosarczyk, A. (2021). Production of antibacterial cement composites containing ZnO/lignin and ZnO– SiO2/lignin hybrid admixtures. Cement and Concrete Composites, 124, 104250. https://doi. org/10.1016/j.cemconcomp.2021.104250 Lee, G. H., Kim, Y. S., Kwon, E., Yun, J. W., & Kang, B. C. (2020). Toxicologic evaluation for amorphous silica nanoparticles: Genotoxic and non-genotoxic tumor-promoting potential. Pharmaceutics, 12(9), 1–17. https://doi.org/10.3390/pharmaceutics12090826 Li, L., Gu, Z., Gu, W., Liu, J., & Xu, Z. P. (2016). Efficient drug delivery using SiO2-layered double hydroxide nanocomposites. Journal of Colloid and Interface Science, 470, 47–55. https:// doi.org/10.1016/J.JCIS.2016.02.042 Liu, M., Shafiq, M., Sun, B., Wu, J., Wang, W., EL-Newehy, M., EL-Hamshary, H., Morsi, Y., Ali, O., Khan, A.  U. R., & Mo, X. (2022). Composite superelastic aerogel scaffolds containing flexible SiO2 nanofibers promote bone regeneration. Advanced Healthcare Materials, 11(15). https://doi.org/10.1002/adhm.202200499 Lozins, R., Selga, T., & Ozoliņš, D. (2020). Microorganism adhesion using silicon dioxide: An experimental study. Heliyon, 6(4), e03678. https://doi.org/10.1016/J.HELIYON.2020.E03678 Mahtabani, A., Rytöluoto, I., Anyszka, R., He, X., Saarimäki, E., Lahti, K., Paajanen, M., Dierkes, W., & Blume, A. (2020). On the silica surface modification and its effect on charge trapping and transport in PP-based dielectric nanocomposites. ACS Applied Polymer Materials, 2(8), 3148–3160. https://doi.org/10.1021/acsapm.0c00349 Mamaeva, V., Sahlgren, C., & Lindén, M. (2013). Mesoporous silica nanoparticles in medicine— Recent advances. Advanced Drug Delivery Reviews, 65(5), 689–702. https://doi.org/10.1016/J. ADDR.2012.07.018 Munir, T., Mahmood, A., Peter, N., Rafaqat, N., Imran, M., & Ali, H. E. (2023). Structural, morphological and optical properties at various concentration of Ag doped SiO2-NPs via sol gel method for antibacterial and anticancer activities. Surfaces and Interfaces, 38, 102759. https:// doi.org/10.1016/j.surfin.2023.102759 Nozari, B., Montazer, M., & Mahmoudi Rad, M. (2021). Stable ZnO/SiO2 nano coating on polyester for anti-bacterial, self-cleaning and flame retardant applications. Materials Chemistry and Physics, 267, 124674. https://doi.org/10.1016/j.matchemphys.2021.124674

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

93

Ogawa, T., Okumura, R., Nagano, K., Minemura, T., Izumi, M., Motooka, D., Nakamura, S., Iida, T., Maeda, Y., Kumanogoh, A., Tsutsumi, Y., & Takeda, K. (2021). Oral intake of silica nanoparticles exacerbates intestinal inflammation. Biochemical and Biophysical Research Communications, 534, 540–546. https://doi.org/10.1016/J.BBRC.2020.11.047 Qiao, H., Xiao, H., Huang, Y., Yuan, C., Zhang, X., Bu, X., Wang, Z., Han, S., Zhang, L., Su, Z., & Zhang, X. (2019). SiO2 loading into polydopamine-functionalized TiO2 nanotubes for biomedical applications. Surface and Coatings Technology, 364, 170–179. https://doi.org/10.1016/j. surfcoat.2019.02.089 Ribas, R. M., de Campos, P. A., de Brito, C. S., & Gontijo-Filho, P. P. (2020). Coronavirus Disease 2019 (COVID-19) and healthcare-associated infections: Emerging and future challenges for public health in Brazil. Travel Medicine and Infectious Disease, 37, 101675. https://doi. org/10.1016/J.TMAID.2020.101675 Ringdalen, E., & Tangstad, M. (2016). Softening and melting of SiO2, an important parameter for reactions with quartz in Si production. In Advances in molten slags, fluxes, and salts: Proceedings of the 10th international conference on Molten Slags, Fluxes and Salts 2016 (pp. 43–51). Springer International Publishing. https://doi.org/10.1007/978-­3-­319-­48769-­4_4 Rizk, M., Sultan, M. A., Tawfik, B. M., & El-Eryan, R. T. (2022). Highly sensitive and selective sensing probe for determination of anti-Covid-19 Remdesvir: Application to pharmaceutical dosage form and biological fluids. Journal of the Electrochemical Society, 169(2), 026522. https://doi.org/10.1149/1945-­7111/ac53ca Romdoni, Y., Kadja, G. T. M., Kitamoto, Y., & Khalil, M. (2023). Synthesis of multifunctional Fe3O4@SiO2-Ag nanocomposite for antibacterial and anticancer drug delivery. Applied Surface Science, 610, 155610. https://doi.org/10.1016/j.apsusc.2022.155610 Salimi, E., & Nigje, A. K. (2022). Investigating the antibacterial activity of carboxymethyl cellulose films treated with novel Ag@GO decorated SiO2 nanohybrids. Carbohydrate Polymers, 298, 120077. https://doi.org/10.1016/j.carbpol.2022.120077 Seré, S., De Roo, B., Vervaele, M., Van Gool, S., Jacobs, S., Seo, J. W., & Locquet, J. P. (2018). Altering the biodegradation of mesoporous silica nanoparticles by means of experimental parameters and surface functionalization. Journal of Nanomaterials, 2018. https://doi. org/10.1155/2018/7390618 Shen, Q., Yang, H., Li, Y., Li, S., Chen, K., Wang, H., & Ma, J. (2022). Rapid determination of antiviral drugs in yellow catfish (Pelteobagrus fulvidraco) using graphene/silica nanospheres (G/KCC-1) based pipette tip solid-phase extraction with ultra-performance liquid chromatography-­tandem mass spectrometry. Journal of Chromatography B, 1189, 123097. https://doi.org/10.1016/j.jchromb.2022.123097 Sheykholeslami, S.  O. R., Khalil-Allafi, J., Etminanfar, M., Khalili, V., & Parsa, A.  B. (2023). Synthesis and development of novel spherical mesoporous SiO2/HA particles and incorporating them in electrodeposited hydroxyapatite coatings for biomedical applications. Surface and Coatings Technology, 459, 129410. https://doi.org/10.1016/j.surfcoat.2023.129410 Sun, B., Feng, Y., Mo, X., Zheng, P., Wang, Q., Li, P., Peng, P., Liu, X., Chen, Z., Huang, H., Zhang, F., Luo, W., Niu, X., Hu, P., Wang, L., Peng, H., Huang, Z., Feng, L., Li, F., et al. (2020). Kinetics of SARS-CoV-2 specific IgM and IgG responses in COVID-19 patients. Emerging Microbes & Infections, 9(1), 940–948. https://doi.org/10.1080/22221751.2020.1762515 Tian, B., & Liu, Y. (2021). Antibacterial applications and safety issues of silica-based materials: A review. International Journal of Applied Ceramic Technology, 18(2), 289–301. https://doi. org/10.1111/ijac.13641 Tng, D. J. H., & Low, J. G. H. (2023). Current status of silica-based nanoparticles as therapeutics and its potential as therapies against viruses. Antiviral Research, 210, 105488. https://doi. org/10.1016/J.ANTIVIRAL.2022.105488 Tran, N. T., Ha, D., Pham, L. H., Vo, T. V., Nguyen, N. N., Tran, C. K., Nguyen, D. M., Nguyen, T. T. T., Van Tran, T. T., Nguyen, P. L. M., & Hoang, D. (2023). Ag/SiO2 nanoparticles stabilization with lignin derived from rice husk for antifungal and antibacterial activities.

94

V. Kokkarachedu et al.

International Journal of Biological Macromolecules, 230, 123124. https://doi.org/10.1016/j. ijbiomac.2022.123124 Tsugita, M., Morimoto, N., & Nakayama, M. (2017). SiO2 and TiO2 nanoparticles synergistically trigger macrophage inflammatory responses. Particle and Fibre Toxicology, 14(1), 11. https:// doi.org/10.1186/s12989-­017-­0192-­6 Tsutsumi-Arai, C., Iwamiya, Y., Hoshino, R., Terada-Ito, C., Sejima, S., Akutsu-Suyama, K., Shibayama, M., Hiroi, Z., Tokuyama-Toda, R., Iwamiya, R., Ijichi, K., Chiba, T., & Satomura, K. (2022). Surface functionalization of non-woven fabrics using a novel silica-resin coating technology: Antiviral treatment of non-woven fabric filters in surgical masks. International Journal of Environmental Research and Public Health, 19(6), 3639. https://doi.org/10.3390/ ijerph19063639 Wan, W., Feng, Y., Yang, J., Xu, S., & Qiu, T. (2015). Preparation of mesoporous silica ceramics with relatively high strength from industrial wastes by low-toxic aqueous gel-casting. Journal of the European Ceramic Society, 35(7), 2163–2170. https://doi.org/10.1016/J. JEURCERAMSOC.2015.01.011 Wang, J., Han, S., Ke, D., & Wang, R. (2012). Semiconductor quantum dots surface modification for potential cancer diagnostic and therapeutic applications. Journal of Nanomaterials, 2012. https://doi.org/10.1155/2012/129041 Wang, C., Yang, X., Gu, B., Liu, H., Zhou, Z., Shi, L., Cheng, X., & Wang, S. (2020). Sensitive and simultaneous detection of SARS-CoV-2-specific IgM/IgG using lateral flow immunoassay based on dual-mode quantum dot nanobeads. Analytical Chemistry, 92(23), 15542–15549. https://doi.org/10.1021/acs.analchem.0c03484 Wang, C., Shi, D., Wan, N., Yang, X., Liu, H., Gao, H., Zhang, M., Bai, Z., Li, D., Dai, E., Rong, Z., & Wang, S. (2021). Development of spike protein-based fluorescence lateral flow assay for the simultaneous detection of SARS-CoV-2 specific IgM and IgG. The Analyst, 146(12), 3908–3917. https://doi.org/10.1039/D1AN00304F Ways, T.  M. M., Ng, K.  W., Lau, W.  M., & Khutoryanskiy, V.  V. (2020). Silica nanoparticles in transmucosal drug delivery. Pharmaceutics, 12(8), 751. https://doi.org/10.3390/ pharmaceutics12080751 Wu, Y., Li, X., Zhong, Q., Wang, F., & Yang, B. (2023). Preparation and filtration performance of antibacterial PVDF/SiO2/Ag composite nanofiber membrane. Journal of Building Engineering, 74, 106864. https://doi.org/10.1016/j.jobe.2023.106864 Yadav, M., Dhanda, M., Arora, R., Ahlawat, S., Singh, G., Nehra, K., & Lata, S. (2023). Dual applicability of ceria and silica nanospheres (CeO2@SiO2 NSs) assembled with pencil graphite electrode to sense ascorbic acid, extended with their antibacterial property. Materials Science and Engineering: B, 297, 116719. https://doi.org/10.1016/j.mseb.2023.116719 Yang, Y., Zhang, M., Song, H., & Yu, C. (2020). Silica-based nanoparticles for biomedical applications: From nanocarriers to biomodulators. Accounts of Chemical Research, 53(8), 1545–1556. https://doi.org/10.1021/acs.accounts.0c00280 Yang, Y., Ding, X., Li, J., Peng, X., Ge, H., Wu, Q., & Wang, X. (2023). Highly stable core-shell structured SiO2@C-Ag composites for organic contaminants degradation and antibacterial application. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 665, 131263. https://doi.org/10.1016/j.colsurfa.2023.131263 Yu, D., Liu, L., Ding, B., Yu, J., & Si, Y. (2023). Spider-web-inspired SiO2/Ag nanofibrous aerogels with superelastic and conductive networks for electroporation water disinfection. Chemical Engineering Journal, 461, 141908. https://doi.org/10.1016/j.cej.2023.141908 Zare, M., Ghomi, E. R., Venkatraman, P. D., & Ramakrishna, S. (2021). Silicone-based biomaterials for biomedical applications: Antimicrobial strategies and 3D printing technologies. Journal of Applied Polymer Science, 138(38). Wiley. https://doi.org/10.1002/app.50969 Zhang, S., Chu, Z., Yin, C., Zhang, C., Lin, G., & Li, Q. (2013). Controllable drug release and simultaneously carrier decomposition of SiO2-drug composite nanoparticles. Journal of the American Chemical Society, 135(15), 5709–5716. https://doi.org/10.1021/ja3123015

SiO2-Based Nanomaterials as Antibacterial and Antiviral Agents: Potential…

95

Zhang, Z., Zhao, L., Ma, Y., Liu, J., Huang, Y., Fu, X., Peng, S., Wang, X., Yang, Y., Zhang, X., Ding, W., Yu, J., Zhu, Y., Yan, H., & Yang, S. (2022). Mechanistic study of silica nanoparticles on the size-dependent retinal toxicity in vitro and in vivo. Journal of Nanobiotechnology, 20(1), 146. https://doi.org/10.1186/s12951-­022-­01326-­8 Zhu, M., Hua, D., Pan, H., Wang, F., Manshian, B., Soenen, S. J., Xiong, R., & Huang, C. (2018). Green electrospun and crosslinked poly(vinyl alcohol)/poly(acrylic acid) composite membranes for antibacterial effective air filtration. Journal of Colloid and Interface Science, 511, 411–423. https://doi.org/10.1016/j.jcis.2017.09.101

CuO Nanoparticles for Antimicrobial/ Antiviral Applications Tippabattini Jayaramudu and Varaprasad Kokkarachedu

Introduction In recent years, the escalating global threat of antimicrobial and antiviral resistance has spurred intensive research into novel strategies to combat, effectively, infectious diseases. The emergence of drug-resistant pathogens and viral strains, poses a significant challenge to conventional therapies, necessitating innovative approaches to safeguard public health. In this pursuit, inorganic nanoparticles (INPs or NPs) have emerged as potent candidates to tackle antimicrobial and antiviral resistance, offering new horizons in the fight against infectious agents (Baig et al., 2021; Paul & Sharma, 2010). INPs are structures engineered at the nanoscale with one-­dimensional shapes and sizes in the range of between 1 and 100 nm, exhibiting unique physicochemical and biological properties that are attributed to their small size and high surface area-to-volume ratio (Khan et al., 2019, 2022). Furthermore, science and nanotechnology have  enhanced the properties of INPs by controlling their size, shape, and during the synthesis process, thereby, enabling the customization of their applications in various fields. INPs have a wide range of applications and are being extensively, researched in material science and nanotechnology (Abbasi et  al., 2023). Their potential to revolutionize various industries and address pressing global challenges make them an exciting area of exploration in modern science and technology. As researchers explore the potential of nanomaterials, particularly in the realm of antimicrobial and antiviral resistance, they hold the promise of T. Jayaramudu Department of Biomedical Engineering, University of Memphis, Memphis, TN, USA V. Kokkarachedu (*) Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_5

97

98

T. Jayaramudu and V. Kokkarachedu

overcoming existing challenges and revolutionizing disease management. In this context, copper-based NPs have gained significant attention for their remarkable antimicrobial and antiviral properties. Their distinctive characteristics, combined with their biocompatibility, make them promising agents in the fight against microbial and viral infections. Copper(Cu) is a versatile and essential inorganic compound that has been integral to human civilization for millennia. Its unique physicochemical properties have made it essential in various applications, ranging from electrical and electronic devices to architecture and medicine. It is a 3d  transition metal, with the atomic chemical symbol “Cu” and an atomic number of 29 that belongs to the Group 11 elements of the periodic table. Cu is a soft and malleable metal with a reddish-­orange color. Cu has been used by humans since ancient times for various applications. First, Egyptians used it for decorative objects and tools. Later it was adopted by the Phoenicians, Greeks, and Romans for the preparation of coins, jewelry, water supply systems, and statues. It is also an essential element for living organisms and plays a significant role in various biological processes. However, Cu forms various oxidation states, i.e., Cu0, CuI, CuII, and CuIII with various environmental conditions (Gawande et al., 2016). Indeed, the oxidation state of Cu, particularly its ability to exist in multiple oxidation states, has sparked considerable interest among research groups worldwide. This unique property allows Cu to participate in diverse chemical reactions and exhibit a broad range of physicochemical characteristics, making it a versatile material for various applications. As a result, researchers have focused on the synthesis of Cu-based materials to harness their potential in a wide array of fields (Fig. 1). This chapter comprehensively, delves into the cutting-edge research and innovative applications of Cu-based NPs in tackling antimicrobial and antiviral resistance.

Fig. 1 Various applications of Cu

CuO Nanoparticles for Antimicrobial/Antiviral Applications

99

We explore the synthesis methods employed for Cu-based NPs, nanocomposites, and its nanostructured materials with tailored properties, designed to combat drug-­ resistant pathogens and viral strains. Understanding the mechanisms through which Cu-based NPs exert their antimicrobial and antiviral effects is vital for guiding the development of effective and targeted interventions. Moreover, the potentials of Cu-based NPs in overcoming multidrug resistance, are succinctly, reviewed. There is a critical problem that hinders the effectiveness of traditional antimicrobial treatments. By exploiting the synergistic interactions of multiple nanomaterial components, researchers are paving the way for novel combination therapies with enhanced antimicrobial and antiviral efficacy.

Synthesis of Copper-Based Nanoparticles The synthesis of NPs can be broadly categorized into two approaches: top-down (starts with larger bulk material and reduces it to the nanoscale) and bottom-up (starts with individual atoms or molecules and assembles them into nanoparticles or nanoscale structures) (Bhavyasree & Xavier, 2022; Jayaramudu et  al., 2022). NPs are of great interest due to their unique properties and potential applications in catalysis, electronics, antimicrobial coatings, and more. The controlled shape, size, and surface properties of the Cu-based NPs can be synthesized by using various methods including physical, chemical, and biological methods. These methods control the size, shape, and surface properties of the formed Cu NPs. However, the physical and chemical processes can produce a high yield of NPs, but they are not suitable to use for biomedical applications due to the use of toxic chemicals, high cost, toxic, etc. Here are some recommended preparation methods for Cu-based NPs and their nanomaterials intended for biomedical applications, which are need to prioritize biocompatibility and control over particle size, shape, and surface properties.

Green Synthesis Green synthesis, also known as bioinspired synthesis or eco-friendly synthesis, refers to the method of preparing NPs or other nanomaterials by using natural, sustainable, and environmentally benign sources as reducing and stabilizing agents. This approach aims to minimize the use of hazardous chemicals and energy-­ intensive processes often associated with traditional synthesis methods (Chakraborty et al., 2022). Green synthesis is particularly attractive for drug delivery, wound healing, and antimicrobial applications due to its potential for producing biocompatible NPs with reduced toxicity (Bhavyasree & Xavier, 2022) (Fig. 2).

100

T. Jayaramudu and V. Kokkarachedu

Fig. 2  Green synthesis of Cu-based nanomaterials (Bhavyasree & Xavier, 2022)

Microemulsion Method The microemulsion method is a versatile and widely used technique for synthesizing NPs, including Cu-based NPs, with precise control over size, shape, and composition. This method involves the use of a stable microemulsion system, consisting of water, oil, and surfactant, to facilitate the formation of NPs (Solanki et al., 2010; Vázquez-Vázquez et  al., 2009). The microemulsion provides a confined environment where chemical reactions occur, leading to the nucleation and growth of Cu-based NPs. The resulting NPs are often stabilized by the surfactant molecules, preventing agglomeration and controlling their dispersity. In this method, Cu-based NPs are prepared within a microemulsion system, where copper ions are reduced in the confined spaces of microemulsion droplets. The nanomaterial’s size can be regulated by modifying the properties of the microemulsion. Microemulsion-­ synthesized Cu-based NPs can be incorporated into coatings to provide antimicrobial properties for medical devices or wound dressings.

Electrochemical Deposition This method, also known as electrodeposition or electroplating, is a versatile and widely used technique for synthesizing various types of NPs, including Cu-based NPs (Zhou et al., 2004). This method involves the controlled reduction of metal ions

CuO Nanoparticles for Antimicrobial/Antiviral Applications

101

from a solution onto an electrode surface in the presence of an electric current. Electrochemical deposition offers several advantages, making it suitable for various applications, including antimicrobial and biomedical purposes.

Biopolymer-Assisted Synthesis Biopolymer-assisted synthesis refers to a method of preparing nanoparticles, including Cu-based NPs, by using biopolymers as both reducing and stabilizing agents (Jayaramudu et al., 2020, 2021, 2022). Biopolymers are natural polymers derived from living organisms, such as proteins, peptides, and polysaccharides. This approach offers several advantages, making it suitable for various applications, particularly in the biomedical field.

Hydrothermal Synthesis Hydrothermal synthesis is a method for producing NPs under controlled high-­ temperature and high-pressure aqueous conditions within a sealed reaction chamber, allowing controlled nucleation and growth of particles from precursor solutions (Giannousi et  al., 2014; Outokesh et  al., 2011). This process enables the precise manipulation of NP size, morphology, and properties, making it valuable for various applications, including in the biomedical field where hydrothermal-synthesized NPs can exhibit enhanced biocompatibility, uniform crystallinity, and tailored functionalities, thus holding promise for antimicrobial coatings, drug delivery, wound healing, bioimaging agents, and biological sensing.

Template-Assisted Synthesis Template-assisted synthesis is a class of techniques to develop the NPs, which involves utilizing pre-existing structures or templates, i.e., polymers, micelles, or dendrimers, as guides for the controlled formation of NPs. Through selective interactions and chemical processes, NPs are formed within or around these templates, allowing precise control over size, shape, and properties (Jayaramudu et al., 2019, 2022). This method offers a versatile approach for tailoring NP  characteristics, making it particularly advantageous for applications such as drug delivery, biological sensing, and imaging, where the template’s unique properties can be harnessed to achieve specific functionalities and enhance performance in biomedical and nanotechnology contexts.

102

T. Jayaramudu and V. Kokkarachedu

Characterization of Cu-Based NPs Copper-based nanoparticles (Cu-based NPs) have garnered significant interest owing to their exceptional physicochemical attributes and diverse applications spanning various domains. Exhibiting insolubility in water and solubility in acids, Cu, an inorganic compound, emerges as a semiconductor material with a narrow bandgap of 1.2–1.9 eV contingent upon its crystalline arrangement, thus underlining its inherent significance. A distinct hallmark of Cu-based NPs is their elevated surface area, which can be finely tailored by controlling particle size and morphology. This amalgamation of unique features positions Cu-based NPs as highly promising candidates across a spectrum of applications, encompassing, but not limited to, photocatalysis, gas sensing, and biomedicine. Given the paramount importance of comprehensively characterizing Cu-based NPs, a suite of techniques is diligently employed to fathom their intrinsic properties and ensure consistent quality. This encompassing approach includes X-ray diffraction (XRD), Scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM-EDS), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS),  photoluminescence spectroscopy (PL), attenuated total reflection-­Fourier transform infrared spectroscopy (ATR-FTIR), and Raman spectroscopy. XRD not only sheds light on the crystal structure of NPs but also facilitates the determination of their crystallite size. Concurrently, SEM and TEM delve into dimensions, shapes, and morphologies, illuminating the intricate facets of these NPs. EDS is used to determine the elemental composition of nanomaterials by detecting characteristic X-rays emitted when they are bombarded with an electron beam. This provides valuable information about the types and concentrations of elements present, crucial for understanding their properties and behavior. XPS analyzes the surface chemistry of nanomaterials, providing information about their elemental composition, chemical state, and electronic state. This is valuable for understanding their surface properties and reactivity. PL spectrum gives information on surface defects on NPs, such as emission peaks. Raman spectroscopy is useful for characterizing NPs by providing information about their vibrational modes, size, shape, structure, purity, and surface properties. ATR-FTIR analysis further peels back the layers, elucidating the functional groups that embellish the surface of Cu-based NPs. Complementary to these techniques, UV–vis spectra leverage the phenomenon of surface plasmon resonance (SPR) to indicate the presence of Cu-based NPs, divulging crucial details about their size, shape, and composition.

UV–Visible Spectra UV–visible spectroscopy is a useful technique for studying the optical properties of cupric oxide or copper oxide (CuO) NPs. Specifically, it can be used to analyze the absorbance and reflectance spectra of CuO NPs in the UV–visible range, typically

CuO Nanoparticles for Antimicrobial/Antiviral Applications

103

between 200 nm and 800 nm. The spectra obtained from this analysis can provide information on the NPs’ size, shape, and distribution. CuO NPs exhibit unique optical properties due to their size-dependent bandgap energy. As the size of the NPs decreases, the bandgap energy increases, resulting in a blue shift in the absorption edge. This blue shift can be observed in the UV–visible spectra as a shift toward shorter wavelengths. Additionally, the spectra can provide information on the plasmonic properties of CuO NPs. CuO NPs exhibit localized surface plasmon resonance (LSPR) in the visible range due to their unique shape and composition. The LSPR can be observed as a broad absorption peak in the visible range of the spectrum. Overall, UV–visible spectroscopy is a valuable tool for characterizing the optical properties of CuO NPs and can provide insights into their size, shape, and distribution. By analyzing the spectra obtained from this technique, researchers can better understand the properties of CuO nanomaterials and their potential applications in different fields.

Advantages and Disadvantages of CuO Advantages  The unique properties of CuO NPs make them highly desirable for use in biomedical applications (Naz et  al., 2023). CuO NPs have been shown to exhibit potent antimicrobial and antiviral activity, making them useful for preventing and treating infections. They have also been investigated for their potential as anticancer agents. One of the unique properties of CuO NPs are their ability to exhibit antioxidant activity. This process can help shield cells from damage affected by free radicals, which are unbalanced molecules that can source cellular damage and contribute to the development of diseases such as cancer, Alzheimer’s disease, and Parkinson’s disease (Lyu et  al., 2021). The antioxidant activity of CuO NPs makes them potentially useful for treating these conditions (Djamila et al., 2022). In addition to their antioxidant properties, CuO NPs have also been shown to exhibit other beneficial properties. For example, they have been investigated for their potential as imaging agents in biomedical applications. Magnetic resonance imaging (MRI) and computed tomography (CT) imaging techniques can readily detect CuO NPs, which enhances their potential for use in various biomedical applications (Alizadeh & Ebrahimzadeh, 2021; Perlman et al., 2015). However, it is important to note that CuO NPs have been reported to be more toxic than copper NPs, particularly at high doses. CuO is considered toxic because it can release copper ions in the body, which can lead to copper poisoning. When copper oxide is ingested or inhaled, it can cause symptoms such as nausea, vomiting, diarrhea, and in severe cases, liver and kidney damage. In contrast, elemental copper (Cu) is an essential nutrient for the body when consumed in appropriate amounts, but excessive intake can also lead to health issues. This means that careful dose control is necessary when using CuO NPs in biomedical applications. Cu NPs also have several unique properties that make them attractive for biomedical applications. One of the most notable advantages of these NPs is their

104

T. Jayaramudu and V. Kokkarachedu

antimicrobial activity. Research has demonstrated that Cu NPs possess strong antibacterial properties that can effectively target a wide range of pathogens, including both gram-positive and gram-negative bacteria (Jayaramudu et  al., 2019). They have also been shown to be effective against viruses and fungi, making them useful for preventing and treating infections. In addition to their antimicrobial properties, Cu NPs have also been shown to have antiviral activity. Studies have demonstrated that Cu NPs have the ability to inhibit the replication of various viruses, including influenza and HIV, making them promising candidates for the development of antiviral therapies (Cortes & Zuñiga, 2020). Another advantage of Cu NPs are their biocompatibility. These NPs are not toxic to living cells and can be used safely in biomedical applications. Studies have demonstrated that Cu NPs can aid in the healing of wounds by encouraging the formation of new blood vessels and facilitating cell migration to the injured area. However, Cu is a relatively inexpensive and abundant metal, and Cu NPs are stable under normal storage conditions. This makes them a cost-effective and practical option for a wide range of biomedical applications. Overall, the unique properties of Cu and CuO NPs make them promising candidates for a wide range of antibacterial, antiviral, and biomedical applications. Ongoing research in this area is likely to uncover even more potential uses for these versatile NPs. Disadvantages  One of the main concerns with CuO NPs are their potential toxicity. According to research, CuO NPs have the potential to induce oxidative stress and cellular damage, which may result in inflammation and harm to tissues. This can be particularly problematic for biomedical applications, where the NPs are intended to interact with living cells and tissues. The toxicity of CuO NPs are thought to be related to their small size and large surface area, which allows them to interact more readily with cells and tissues. In addition, CuO NPs can release copper ions into the surrounding environment, which can further contribute to their toxicity. Another disadvantage of CuO NPs are their tendency to aggregate, or clump together, which can reduce their effectiveness as antimicrobial or antiviral agents. This aggregation can also make it difficult to control the dose of the NPs, which is important for minimizing toxicity and ensuring their effectiveness. Furthermore, when CuO NPs aggregate, they can form larger particles that may be harder for the body to eliminate and could accumulate in tissues over time. This accumulation could potentially lead to adverse health effects, highlighting the importance of careful consideration when utilizing CuO NPs in various applications. Finally, the long-term effects of exposure to CuO NPs are not yet fully understood, and more research is needed to fully assess their safety for use in antibacterial, antiviral, and biomedical applications. CuO NPs have potential uses in various areas, but their risks and limitations should be carefully considered before clinical use. However, it is important to note that CuO NPs have been reported to be more toxic than Cu NPs, particularly at high doses. This means that careful dose control is necessary when using CuO nanoparticles in biomedical applications. It is also important to note that the long-term effects of exposure to CuO are not yet fully understood, and more research is needed to fully assess their safety for use in

CuO Nanoparticles for Antimicrobial/Antiviral Applications

105

biomedical applications. Overall, Cu and CuO NPs possess unique properties that make them promising candidates for a variety of biomedical applications. While CuO NPs have some additional advantages, their potential toxicity means that they must be used with caution. Further research is needed to fully understand the potential uses and risks associated with these NPs in biomedical applications.

Toxicity Effect (a Mechanism) on Living Cells In addition to their potential toxicity on living cells, it is important to note that the toxicity of CuO NPs can differ based on the type of cells and tissues they interact with. For example, studies have shown that CuO NPs can cause more toxicity in lung cells compared to other cell types (Moschini et al., 2023). This highlights the importance of carefully, studying the toxicity of CuO NPs in different cell and tissue types to fully understand their potential risks and limitations. Furthermore, it is important to consider the potential interactions between CuO NPs and normal cells when studying their toxicity (Jing et al., 2015). Normal cells are critical for maintaining the health and function of the body, and any disruption to their function can have significant consequences. While CuO NPs may have antimicrobial or antiviral properties, it is important to carefully consider their potential effects on normal cells when developing biomedical applications. Mechanism  CuO NPs have been shown to exhibit potential toxicity on living cells, making it crucial to understand the underlying mechanisms for safe and effective biomedical applications. One of the primary mechanisms by which CuO NPs induce toxicity is through the generation of reactive oxygen species (ROS) (Chang et al., 2012). ROS are prominently reactive molecules, which can interact with cellular components, including proteins, lipids, and DNA, leading to cellular damage and dysfunction (Sajjad et  al., 2023). CuO NPs can generate ROS through various mechanisms, including the Fenton reaction, where copper ions react with hydrogen peroxide to produce hydroxyl radicals. These radicals further react with cellular components, causing oxidative stress and subsequent cellular damage. It is important to note that the toxicity of CuO NPs may vary depending on cell and tissue types, as well as the size, shape, and surface properties of the NPs. Therefore, comprehensive studies are necessary to understand the potential risks and limitations of CuO NPs in different contexts. Additionally, when developing biomedical applications, careful consideration should be given to potential interactions between CuO NPs and normal cells to ensure their impact on overall cellular health and function is thoroughly evaluated (Fig. 3). Several methods can be used to study the toxicity of CuO NPs in normal cells (Naz et al., 2020). In addition to the assays mentioned earlier, the MTT (3-(4,5-­dim ethylthiazol-­2-yl)-2,5-diphenyltetrazolium bromide assay, is a commonly used colorimetric assay for assessing cell viability and proliferation) assay or the trypan blue exclusion assay, other assays can be used to assess the effects of CuO NPs on

106

T. Jayaramudu and V. Kokkarachedu

Fig. 3  CuO NPs have been shown to cause toxicity (Sajjad et al., 2023)

cellular function (Karthikeyan et  al., 2021, 2023; Strober, 2015). For example, assays that measure changes in gene expression or protein levels can provide insight into the mechanisms by which CuO NPs affect normal cells. To study the interactions between CuO NPs and normal cells, imaging techniques, e.g., TEM or confocal microscopy can be employed. These techniques enable visualization of the cellular response to CuO NPs and provide insights into their potential effects on cells and tissues. In vivo studies can also be used to assess the toxicity of CuO NPs. These studies involve the administration of CuO NPs to animals and the measurement of their effects on various parameters, such as organ function, inflammation, and oxidative stress. Animal studies can provide valuable information about the potential toxicity of CuO NPs in living organisms and can help to guide the development of safe and effective biomedical applications. Overall, the understanding of the potential toxicity of CuO NPs on normal cells is critical for developing safe and effective biomedical applications. By carefully studying the mechanisms by which CuO NPs interact with living cells, researchers can identify the potential risks and limitations and develop strategies to minimize their impact on normal cellular function.

CuO-Based Materials for Antiviral (COVID-19) Applications CuO has been shown to have antiviral properties. When used as a coating material on surfaces, it can inhibit virus from entering cells and spreading (Singh, 2023). However, CuO suspensions have been shown to be highly effective in deactivating

CuO Nanoparticles for Antimicrobial/Antiviral Applications

107

the human coronavirus and other types of viruses. In a (Abulikemu et  al., 2022) study, commercially available CuO NP suspensions were able to deactivate over 99.55% of the human coronavirus 229E within just 30 min of exposure (Abulikemu et al., 2022). This highlights the potent antiviral properties of CuO and its potential application in mitigating the spread of coronaviruses. Cu has been known for centuries to have antimicrobial characteristics and has been employed in several applications, including in hospitals and other healthcare settings. CuO suspensions could potentially be used in a variety of settings to help prevent the spread of viruses, including in healthcare facilities, public transportation, and other high-traffic areas. While more research is needed to fully understand the effectiveness of CuO suspensions against the coronavirus and other viruses, the initial results are promising and suggest that this could be a suitable tool in the fight beside infectious diseases. Recent reports have shown that standard polymers have been found to promote COVID-19 virus viability for up to 3 days. In contrast, Cu surfaces have been shown to reduce viral viability to only 4 h (Zuniga & Cortes, 2020). To address this problem, researchers have enhanced the antimicrobial mechanism of nano CuO by reducing the size of the CuO to the nanoscale (5–10 nm) and increasing the volume of Cu concentration that can be coated with poly-based materials (Ermini & Voliani, 2021; Fan et al., 2021; Naika et al., 2015). This increases the total surface area of the particles, releasing a higher amount of metal ions. The second factor that enhances the antimicrobial effect is the incorporation of nano CuO into biopolymer matrices (Toledo et al., 2022). Nano CuO on a polymer structure presents a potent antimicrobial influence than microparticles or metal surfaces by facilitating the adsorption of microorganisms on the polymer surface and initiating the diffusion of water via the polymeric biomaterials. Water with dissolved oxygen spreads the surface of surrounded nano Cu, allowing the corrosion process to take effect by releasing Cu ions. These Cu ions reach the composite surface, damaging the microorganism cell membrane, allowing the metal ions to enter the cell and damage DNA, RNA, and other biomolecules (Sportelli et al., 2020). The Cu ions and associated OH radicals produce DNA denaturation, damaging helical structures. Theis DNA and RNA damage has been shown to deactivate viruses. Researchers have been working on developing biodegradable nanofibrous hybrid materials using a combination of polyvinyl alcohol and CuO (Alshabanah et  al., 2021). These materials have shown promising abilities to control both COVID-19 and multidrug-resistant bacteria. The nanofibrous hybrid members have a size range of approximately 200–250 nm. The researchers observed that as the CuO content in the hybrid members is increased (ranging from 5% to 9%), the materials’ antiviral (COVID-19) and antibacterial properties improve significantly. The inclusion of metal oxide, such as CuO, in the polymer material enhances its antiviral and antibacterial properties. This suggests that metal oxide plays a crucial role in improving the overall efficacy of the hybrid members in combating viral and bacterial infections. By leveraging these biodegradable nanofibrous hybrid members, there is potential to develop advanced materials that can effectively control COVID-19 and multidrug-resistant bacteria, offering new solutions in healthcare and infection control.

108

T. Jayaramudu and V. Kokkarachedu

Due to COVID-19, face masks have increased in our lives. According to the reports, a regular face mask cannot stop the virus termination. Therefore, they created different masks with effective filters. However, several researchers discuss the importance of air filters in controlling the spread of viral aerosols, specifically in the circumstances of the COVID-19 virus (Mallakpour et al., 2022). The authors propose the use of advanced air filters that incorporate metal oxides, especially CuO NPs, to enhance filtration efficiency. CuO has been found to have antimicrobial properties and can help capture and deactivate viruses, thus improving the effectiveness of air filters in preventing the spread of viral aerosols. The paper describes the fabrication process of these filters and presents experimental data on their filtration performance. Overall, the study suggests that air filters with CuO NPs have great potential in mitigating the spread of COVID-19 and other viral diseases. CuO-coated air filters in vehicles and other air-conditioning systems could have potent effects on public health, especially in the COVID-19 pandemic (Perelshtein et al., 2022). Airborne transmission of the virus is a major concern, and improving indoor air quality is a vital strategy for reducing the risk of infection. The use of CuO NPs in air filters could be an effective way to capture and deactivate viral particles, thus reducing the spread of the virus through the air. The study involved coating air filters in vehicles with CuO NPs using a roll-to-roll coating method (Perelshtein et al., 2022). The coated filters were found to be effective against various types of bacteria and viruses, including E. coli, Staphylococcus aureus, H1N1 influenza, and two SARS-CoV-2 variants. The coating was also found to be stable and did not affect the filtering properties of the air filters. The authors suggest that this method could be expanded to other air-conditioning systems. This approach could be particularly useful in settings such as hospitals, schools, and public transportation systems, where the risk of airborne transmission is high. Further research is needed to fully understand the effectiveness of CuO-coated air filters in different settings, but the initial results are promising and suggest that this could be an important tool in the fight against COVID-19 and other viral diseases. The process described by Wu et al. for creating a copper film on a glass substrate using a complex reduction method shows promise in potentially inactivating the SARS-CoV-2 virus (Wu et al., 2022). If proven effective, the copper film could have significant implications for preventing the spread of COVID-19 by coating high-­ touch surfaces. Scaling up the production of the copper film could make it an affordable and practical solution for reducing transmission risks.

Enhancing Antibacterial Properties of CuO Nanoparticles CuO is a material that has gained attention for its antimicrobial properties. However, studies have shown that it has broad-spectrum antimicrobial activity against various microorganisms, including bacteria, viruses, and fungi. However, there are several

CuO Nanoparticles for Antimicrobial/Antiviral Applications

109

ways in which the antimicrobial properties of CuO can be improved. Methods such as reducing particle size or increasing porosity can be used to increase the surface area of CuO NPs and enhance their antimicrobial properties. Ball milling, precipitation, sol–gel, hydrothermal, and microwave-assisted synthesis are techniques that can be used to reduce particle size (Dubadi et al., 2023; Li et al., 2021; Varaprasad et  al., 2020). Increasing porosity can be achieved using templates or sacrificial materials during synthesis. These methods create more active sites for interaction with microorganisms, leading to improved antimicrobial properties. Functionalizing the surface of CuO NPs with amino or carboxyl groups can significantly enhance their antimicrobial activity (Badetti et  al., 2019; Ontiveros-­ Robles et al., 2023; Pandiyarajan et al., 2013). The amino and carboxyl groups can create a positive or negative charge on the surface of the NPs, respectively, which can interact with the negatively charged microbial cell membranes. This interface can lead to the interference of the cell membrane and, ultimately, the death of the microorganisms. Moreover, the functionalization process can be achieved through various methods such as chemical modification, electrostatic adsorption, or physical absorption. These methods can provide a stable and uniform coating of functional groups on CuO NPs’ surface, improving their biocompatibility and reducing their toxicity. The dispersion of CuO NPs in solution is critical to ensure its effectiveness as an antimicrobial agent. To enhance the dispersion, surfactants or other stabilizing agents can be used. These agents help to prevent the agglomeration of CuO particles, which can lead to uneven distribution and reduced efficacy. Another strategy to improve the antimicrobial properties of CuO is to increase its concentration. However, it is essential to ensure that the concentration is safe and non-toxic to human cells or other non-target organisms. Careful consideration of the concentration and its potential impact on living systems is necessary to avoid any adverse effects. Combining CuO with other antimicrobial agents such as silver, nickel oxide, zinc oxide NPs, or antibiotics can enhance its effectiveness against a wider range of microorganisms. This approach has been shown to have synergistic effects and improve overall antimicrobial activity, making it a promising strategy for developing new antimicrobial materials. Finally, combining CuO with other antimicrobial agents can enhance its effectiveness against a wider range of microorganisms. For example, combining CuO with silver, nickel oxide, zinc oxide, carbon nanotube, graphene oxide, and other NPs or antibiotics is effective against both bacteria and viruses (Ahmadi et al., 2021; Bhosale et al., 2023; Ji et al., 2023; Zhang et al., 2023, 2018). In conclusion, there are several ways in which the antimicrobial properties of CuO can be improved. By increasing the surface area, enhancing the surface with functional groups, improving dispersion, increasing concentration, and combining with other agents, CuO can be made even more effective against a wide range of microorganisms.

110

T. Jayaramudu and V. Kokkarachedu

Recent Studies on Antimicrobial Applications CuO exhibits antimicrobial properties due to its ability to release copper ions (Cu2+) when in contact with moisture or certain organic compounds. These released copper ions disrupt the cell membranes of microorganisms, leading to their death. CuO has a broad-spectrum antimicrobial effect, making it effective against various pathogens, including antibiotic-resistant strains. Its use in coatings for medical devices, textiles, and healthcare surfaces shows promise in reducing the spread of infections and improving hygiene. Karampoor et al. reported a study on the preparation of a self-healing coating that contains CuO and has antibacterial properties (Karampoor et al., 2023). The coating is made from a combination of polyurea-formaldehyde and linseed oil. The researchers found that adding CuO (4  g/L) to the coating improved its antibacterial properties (against S. aureus and E. coli) while enhancing its self-healing ability. This makes the coating useful for applications where bacterial growth is a concern, such as in healthcare facilities or food processing plants. Overall, the study provides insights into the development of new coatings with advanced functionalities that can improve performance and safety in various industries. Lately, the study found that cuprous oxide-coated and cupric oxide-coated surfaces have antimicrobial properties that can help to control the growth of various types of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), and Staphylococcus aureus (S. aureus) (Behzadinasab et al., 2022). These bacteria are commonly found in healthcare settings and can cause infections in patients with weakened immune systems. In addition to bacteria, the study also found that these coatings have antifungal properties that can help control fungi growth such as Candida albicans. Cu2O and CuO coatings are biocompatible with human monocytes and murine fibroblasts (via lactate dehydrogenase assay). However, the non-­ toxic surface copper-based coatings are developed with polyurethane, which binds the active CuO and is generated via heat treatment of Cu2O. Overall, the study suggests that these coatings could be useful in various settings where controlling the growth of microorganisms is important. In order to obtain effective antibacterial nanomaterials, researchers used different molecular-weight polymers, leaf extracts, and microwave-assisted methods (Jayaramudu et  al., 2023; Kartikeyan et  al., 2023; Raghavendra et  al., 2016). Krkobabic et al. have reported the development of antimicrobial nanocomposites based on oxidized cotton fabric and in situ biosynthesized CuO nanostructures using bearberry leaves extract (Krkobabić et al., 2022). The study aimed to develop a sustainable, eco-friendly approach to creating antimicrobial textiles. In this investigation, the researchers used bearberry leaves extract to biosynthesize CuO NPs in situ on the oxidized cotton fabric. The CuO NPs were characterized using various techniques, including X-ray diffraction and scanning electron microscopy. The results showed that the CuO NPs were homogeneously diffuse on the fabric surface and had a normal size of 30–50  nm. The antimicrobial activity of the

CuO Nanoparticles for Antimicrobial/Antiviral Applications

111

nanocomposites was evaluated against two bacterial strains, E. coli and S. aureus, using the disk diffusion method. The results showed that the nanocomposites exhibited significant antimicrobial activity against both bacterial strains. Furthermore, the nanocomposites showed good washing durability, retaining their antimicrobial activity even after multiple washes. The researchers also evaluated the cytotoxicity of the nanocomposites using human dermal fibroblast cells and found that they were non-toxic. The study suggests that oxidized cotton fabric-based nanocomposites with in situ biosynthesized CuO NPs using bearberry leaves extract could be a promising approach for developing sustainable and eco-friendly antimicrobial textiles. Aggrawal et al., prepared an effective antimicrobial CuO nanoflakes encapsulated cellulose paper via microwave-assisted methods, which is an efficient and eco-friendly approach (Aggrawal et al., 2022). The paper matrices’ antimicrobial activity (antibacterial and antifungal behavior) was evaluated against E. coli and Gloeophyllum trabeum. The results showed that the paper matrices exhibited significant antimicrobial activity against both bacterial strains. In addition, they noticed that when the paper’s CuO content (5–30%) increases, its antimicrobial properties also increase. Overall, the study suggests that microwave-assisted ultrafast immobilization of CuO nanostructures in paper matrices could be a promising approach for developing antimicrobial paper products. This efficient, eco-friendly approach could have important implications for various applications, including food packaging and medical products. The study conducted by Rajendaran et al., is significant as it demonstrates the potential of using natural extracts for the green synthesis of CuO-based NPs with excellent antimicrobial and photocatalytic activities (Rajendaran et al., 2019). The use of Azadirachta indica leaf extracts as a nucleation agent for the synthesis of Ag-Mo/CuO NPs is an innovative and environmentally friendly approach that avoids the use of harmful chemicals and solvents. The small size of the synthesized NPs (11.23 nm) is also noteworthy, as it can enhance their reactivity and increase their surface area, improving their photocatalytic and antimicrobial properties. The results of the study showed that the synthesized NPs had higher photocatalytic activity (99%) than pure CuO (39%) and excellent antimicrobial activity against various pathogenic microorganisms, including bacteria and fungi. Overall, this study has important implications for the development of sustainable and effective nanomaterials for various applications, including water treatment, biomedical, and environmental remediation. Hasanin et al. prepared an eco-friendly and bioactive film that is used for active packaging applications (Hasanin & Youssef, 2022). The film is composed of biopolymers poly(butylene adipate-co-terephthalate) doped with CuO NPs and reinforced with enzymatically modified nanocellulose fibers. The film is capable of releasing bioactive compounds that can improve the shelf life of food and reduce the risk of microbial contamination. Additionally, the film is environmentally friendly as it is made from renewable and biodegradable materials. The study conducted by Karthikeyan et al. focused on the preparation and evaluation of biocidal activities of chitosan/CuO nanomaterials (CCuO NM) synthesized

112

T. Jayaramudu and V. Kokkarachedu

through a green process (Karthikeyan et al., 2021). The top idea was to study the effectiveness of these nanomaterials in eliminating both bacterial cells and cancer cells. In this study, the researchers combined chitosan with CuO NPs, which are known to exhibit potential cytotoxic effects against cancer cells. By incorporating CuO NPs into the chitosan matrix, the researchers aimed to enhance the biocidal properties of the nanomaterial. The synergistic effects of chitosan and CuO NPs could potentially lead to greater antimicrobial activity against bacterial cells and cytotoxicity against cancer cells. One notable aspect of this study is the use of a green synthesis process. Green synthesis involves employing environmentally friendly approaches to minimize the environmental impact associated with traditional synthesis methods. This typically includes using sustainable materials, reducing or eliminating the use of hazardous chemicals, and adopting energy-efficient techniques.

 uture Prospects of CuO as an Antimicrobial F and Antiviral Agent CuO is a compound that has garnered significant attention in recent years due to its potential antimicrobial and antiviral properties. This has prompted extensive research into its various applications and future prospects. In this examination, we will survey the potential expansion of CuO, its antimicrobial and antiviral properties, and the implications for different industries. CuO has shown promising results in inhibiting the growth of bacteria and viruses. Studies have demonstrated its effectiveness against common pathogens, such as E. coli and S. aureus. The antimicrobial activity of CuO is attributed to its ability to release copper ions, which can disrupt the integrity of bacterial and viral membranes, leading to their destruction. Additionally, CuO NPs have been found to possess antiviral properties against influenza viruses, offering potential in the fight against viral infections. One area where CuO could have a significant impact is in the medical field. Medical devices, such as catheters and implants, are prone to bacterial colonization, leading to infections. Incorporating CuO coatings or nanoparticles into these devices could help prevent bacterial growth and reduce the risk of infections. Furthermore, CuO-infused wound dressings have shown promise in promoting wound healing and preventing infection. The use of CuO in medical settings may help reduce the reliance on antibiotics, potentially mitigating the development of antibiotic resistance. Beyond healthcare, CuO also holds potential in air and water purification systems. Airborne bacteria and viruses can be effectively neutralized by CuO NPs, offering a promising solution for improving indoor air quality. In water treatment, CuO has demonstrated its ability to eliminate harmful microorganisms, making it a viable option for disinfection purposes. However, it is crucial to consider the potential environmental impact of by using CuO NPs in these applications and ensure proper disposal methods to prevent any unintended consequences.

CuO Nanoparticles for Antimicrobial/Antiviral Applications

113

Another area where CuO could find application is in textiles. By incorporating CuO NPs into fabrics, it may be possible to create antimicrobial and antiviral clothing. This could be particularly beneficial in settings where maintaining hygiene is crucial, such as the hospitals or the food processing facilities. Antimicrobial textiles could help reduce the transmission of infections and improve overall safety. While the potential applications of CuO are promising, it is important to acknowledge the need for further research. Understanding the long-term effects of CuO NPs on human health and the environment is paramount. It is crucial to assess any potential risks associated with their use and develop appropriate safety guidelines. However, researchers are exploring the use of CuO NPs in various other fields, such as energy storage and catalysis. CuO has shown promise as an electrode material for lithium-­ ion batteries, with its high capacity and stability. Additionally, CuO NPs have demonstrated excellent catalytic activity in chemical reactions, making them a potential catalyst in industrial processes. The versatility of CuO and its potential for innovation in different sectors, make it an exciting area of research with promising future prospects. In conclusion, CuO holds great promise as an antimicrobial and antiviral agent. Its potential applications span across various industries, including healthcare, air and water purification, and textiles. However, further research is necessary to fully explore its capabilities, address safety concerns, and ensure responsible use. With continued investigation and development, CuO may play a significant role in combating microbial infections and improving public health in the future. In the future, the applications of Cu-based NPs are expected to expand even further. Ongoing research and advancements in nanotechnology will likely uncover new ways to utilize the unique properties of Cu-based NPs. This could lead to breakthroughs in areas, such as regenerative medicine, where these NPs may play a role in tissue engineering and organ transplantation. Additionally, the integration of Cu-based NPs into wearable devices and implantable sensors could revolutionize healthcare monitoring and diagnostics. Furthermore, the development of more sustainable and efficient methods for the synthesis and production of Cu-based NPs, will no doubt, contribute to their widespread adoption in various industries. Overall, the future holds tremendous potential for Cu-based NPs to continue driving innovation and making a significant impact across diverse fields.

Conclusion In conclusion, the utilization of CuO-base NPs for antimicrobial and antiviral applications, represents a ground-breaking avenue in the ongoing battle against microbial infections and viral diseases. These NPs exhibit a unique combination of physicochemical attributes that enable them to combat pathogens effectively. Their ability to release copper ions in a controlled manner grants them potent antimicrobial properties, disrupting cell membranes, interfering with crucial enzymatic processes, and inducing oxidative stress. This multifaceted approach presents a promising solution, particularly in the face of antibiotic-resistant strains and

114

T. Jayaramudu and V. Kokkarachedu

emerging viral threats. The remarkable success of Cu-based NPs in inhibiting the growth of bacteria, fungi, and viruses highlights their potential to revolutionize the field of infection control. Additionally, their compatibility with targeted drug delivery systems and diagnostic imaging further expands their utility in personalized medicine. However, as with any emerging technology, rigorous research into their safety, potential toxicity, and environmental impact is essential to ensure their responsible application. By capitalizing on the extraordinary characteristics of Cu-based NPs, the scientific community is paving the way for innovative and effective strategies that have the potential to reshape the landscape of healthcare, offering a new hope in the ongoing endeavor to safeguard human health against microbial and viral threats. Further research is however, needed to fully understand the properties and potential applications of Cu-based NPs. Acknowledgments  KVP wishes to acknowledge Fondecyt Regular Project No. 1211118, ANID, and FIT, USS, Chile.

References Abbasi, R., Shineh, G., Mobaraki, M., Doughty, S., & Tayebi, L. (2023). Structural parameters of nanoparticles affecting their toxicity for biomedical applications: A review. Journal of Nanoparticle Research, 25(3), 43. https://doi.org/10.1007/s11051-­023-­05690-­w Abulikemu, M., Booker, E. P., Tabrizi, E. A. B., & Jabbour, G. E. (2022). Fast and effective deactivation of human coronavirus with copper oxide suspensions. ACS Applied Bio Materials, 5(8), 3734–3740. https://doi.org/10.1021/acsabm.2c00229 Aggrawal, S., Pradhan, D., & Mohanty, P. (2022). Microwave assisted ultrafast immobilization of CuO nanostructures in paper matrices for antimicrobial applications. Cellulose, 29(4), 2633–2643. https://doi.org/10.1007/s10570-­022-­04457-­1 Ahmadi, R., Fatahi, R. F. N., Sangpour, P., Bagheri, M., & Rahimi, T. (2021). Evaluation of antibacterial behavior of in situ grown CuO-GO nanocomposites. Materials Today Communications, 28, 102642. https://doi.org/10.1016/j.mtcomm.2021.102642 Alizadeh, S.  R., & Ebrahimzadeh, M.  A. (2021). Characterization and anticancer activities of green synthesized CuO nanoparticles, a review. Anti-Cancer Agents in Medicinal Chemistry, 21(12), 1529–1543. https://doi.org/10.2174/1871520620666201029111532 Alshabanah, L. A., Hagar, M., Al-Mutabagani, L. A., Abozaid, G. M., Abdallah, S. M., Ahmed, H., Hassanin, A. H., & Shehata, N. (2021). Biodegradable nanofibrous membranes for medical and personal protection applications: Manufacturing, anti-COVID-19 and anti-multidrug resistant bacteria evaluation. Materials, 14(14), 3862. https://doi.org/10.3390/ma14143862 Badetti, E., Calgaro, L., Falchi, L., Bonetto, A., Bettiol, C., Leonetti, B., Ambrosi, E., Zendri, E., & Marcomini, A. (2019). Interaction between copper oxide nanoparticles and amino acids: Influence on the antibacterial activity. Nanomaterials, 9(5), 792. https://doi.org/10.3390/ nano9050792 Baig, N., Kammakakam, I., & Falath, W. (2021). Nanomaterials: A review of synthesis methods, properties, recent progress, and challenges. Materials Advances, 2(6), 1821–1871. https://doi. org/10.1039/D0MA00807A Behzadinasab, S., Hosseini, M., Williams, M. D., Ivester, H. M., Allen, I. C., Falkinham, J. O., & Ducker, W. A. (2022). Antimicrobial activity of cuprous oxide-coated and cupric oxide-coated surfaces. Journal of Hospital Infection, 129, 58–64. https://doi.org/10.1016/j.jhin.2022.07.022

CuO Nanoparticles for Antimicrobial/Antiviral Applications

115

Bhavyasree, P.  G., & Xavier, T.  S. (2022). Green synthesised copper and copper oxide based nanomaterials using plant extracts and their application in antimicrobial activity: Review. Current Research in Green and Sustainable Chemistry, 5(December 2021), 100249. https:// doi.org/10.1016/j.crgsc.2021.100249 Bhosale, S. R., Shinde, S. B., Bhosale, R. R., Dhengale, S. D., Moyo, A. A., Dhavale, R. P., & Anbhule, P. V. (2023). Antibacterial efficacy of NiO composites with CuO nanoclusters via co-precipitation method. Inorganic Chemistry Communications, 155, 111059. https://doi. org/10.1016/j.inoche.2023.111059 Chakraborty, N., Banerjee, J., Chakraborty, P., Banerjee, A., Chanda, S., Ray, K., Acharya, K., & Sarkar, J. (2022). Green synthesis of copper/copper oxide nanoparticles and their applications: A review. Green Chemistry Letters and Reviews, 15(1), 187–215. https://doi.org/10.108 0/17518253.2022.2025916 Chang, Y.-N., Zhang, M., Xia, L., Zhang, J., & Xing, G. (2012). The toxic effects and mechanisms of CuO and ZnO nanoparticles. Materials, 5(12), 2850–2871. https://doi.org/10.3390/ ma5122850 Cortes, A. A., & Zuñiga, J. M. (2020). The use of copper to help prevent transmission of SARS-­ coronavirus and influenza viruses. A general review. Diagnostic Microbiology and Infectious Disease, 98(4), 115176. https://doi.org/10.1016/j.diagmicrobio.2020.115176 Djamila, B., Eddine, L. S., Abderrhmane, B., Nassiba, A., & Barhoum, A. (2022). In vitro antioxidant activities of copper mixed oxide (CuO/Cu2O) nanoparticles produced from the leaves of Phoenix dactylifera L. Biomass Conversion and Biorefinery. https://doi.org/10.1007/ s13399-­022-­02743-­3 Dubadi, R., Huang, S. D., & Jaroniec, M. (2023). Mechanochemical synthesis of nanoparticles for potential antimicrobial applications. Materials, 16(4), 1460. https://doi.org/10.3390/ ma16041460 Ermini, M. L., & Voliani, V. (2021). Antimicrobial nano-agents: The copper age. ACS Nano, 15(4), 6008–6029. https://doi.org/10.1021/acsnano.0c10756 Fan, X., Yahia, L., & Sacher, E. (2021). Antimicrobial properties of the Ag, Cu nanoparticle system. Biology, 10(2), 137. https://doi.org/10.3390/biology10020137 Gawande, M. B., Goswami, A., Felpin, F.-X., Asefa, T., Huang, X., Silva, R., Zou, X., Zboril, R., & Varma, R. S. (2016). Cu and Cu-based nanoparticles: Synthesis and applications in catalysis. Chemical Reviews, 116(6), 3722–3811. https://doi.org/10.1021/acs.chemrev.5b00482 Giannousi, K., Lafazanis, K., Arvanitidis, J., Pantazaki, A., & Dendrinou-Samara, C. (2014). Hydrothermal synthesis of copper based nanoparticles: Antimicrobial screening and interaction with DNA. Journal of Inorganic Biochemistry, 133, 24–32. https://doi.org/10.1016/j. jinorgbio.2013.12.009 Hasanin, M.  S., & Youssef, A.  M. (2022). Ecofriendly bioactive film doped CuO nanoparticles based biopolymers and reinforced by enzymatically modified nanocellulose fibers for active packaging applications. Food Packaging and Shelf Life, 34, 100979. https://doi.org/10.1016/j. fpsl.2022.100979 Jayaramudu, T., Varaprasad, K., Pyarasani, R. D., Reddy, K. K., Kumar, K. D., Akbari-Fakhrabadi, A., Mangalaraja, R. V. V., & Amalraj, J. (2019). Chitosan capped copper oxide/copper nanoparticles encapsulated microbial resistant nanocomposite films. International Journal of Biological Macromolecules, 128, 499–508. https://doi.org/10.1016/j.ijbiomac.2019.01.145 Jayaramudu, T., Varaprasad, K., Reddy, K. K., Pyarasani, R. D., Akbari-Fakhrabadi, A., & Amalraj, J. (2020). Chitosan-pluronic based Cu nanocomposite hydrogels for prototype antimicrobial applications. International Journal of Biological Macromolecules, 143(June), 825–832. https://doi.org/10.1016/j.ijbiomac.2019.09.143 Jayaramudu, T., Varaprasad, K., Pyarasani, R. D., Reddy, K. K., Akbari-Fakhrabadi, A., Carrasco-­ Sánchez, V., & Amalraj, J. (2021). Hydroxypropyl methylcellulose-copper nanoparticle and its nanocomposite hydrogel films for antibacterial application. Carbohydrate Polymers, 254(June 2020), 117302. https://doi.org/10.1016/j.carbpol.2020.117302

116

T. Jayaramudu and V. Kokkarachedu

Jayaramudu, T., Varaprasad, K., Reddy, K. K., Sisubalan, N., Patil, A. J., Sadiku, E. R., & Adamus, G. (2022). Polymers used in green synthesis of nanoparticles and their importance in pharmaceutical and biomedical applications. In Polymeric biomaterials for healthcare applications (Vol. 53, Issue 9, pp.  125–163). Elsevier. https://doi.org/10.1016/B978-­0-­323-­85233-­ 3.00004-­5. Jayaramudu, T., Varaprasad, K., Godzierz, M., Hercog, A., & Adamus, G. (2023). Effect of molecular weight on the shape of polyethyleneimine capped CuO nanoparticles. Materials Letters, 334, 133694. https://doi.org/10.1016/j.matlet.2022.133694 Ji, X., Wu, Y., Han, Y., Liang, B., Cheng, Y., Zheng, J., Guo, S., Li, C., & Xu, H. (2023). Synergistic antibacterial study of nano-Cu2O/CuO@Ag-tetracycline composites. Materials Chemistry and Physics, 306, 127904. https://doi.org/10.1016/j.matchemphys.2023.127904 Jing, X., Park, J. H., Peters, T. M., & Thorne, P. S. (2015). Toxicity of copper oxide nanoparticles in lung epithelial cells exposed at the air–liquid interface compared with in vivo assessment. Toxicology In Vitro, 29(3), 502–511. https://doi.org/10.1016/j.tiv.2014.12.023 Karampoor, M.  R., Atapour, M., & Bahrami, A. (2023). Preparation of an anti-bacterial CuO-­ containing polyurea-formaldehyde/linseed oil self-healing coating. Progress in Organic Coatings, 184, 107879. https://doi.org/10.1016/j.porgcoat.2023.107879 Karthikeyan, C., Varaprasad, K., Venugopal, S. K., Shakila, S., Venkatraman, B. R. R., & Sadiku, R. (2021). Biocidal (bacterial and cancer cells) activities of chitosan/CuO nanomaterial, synthesized via a green process. Carbohydrate Polymers, 259(August 2020), 117762. https://doi. org/10.1016/j.carbpol.2021.117762 Karthikeyan, C., Varaprasad, K., Kim, S., Kumar Jangid, A., Lee, W., Hameed, A. S. H., & Kim, K. (2023). Size-dependent cellular uptake of sodium alginate passivated tin dioxide nanoparticles in triple-negative breast cancer cells. Journal of Industrial and Engineering Chemistry, 123, 476–487. https://doi.org/10.1016/j.jiec.2023.04.001 Kartikeyan, C., Aepuru, R., Varaprasad, K., Tiwari, N., Sahoo, P. K., Jayaramudu, T., Sanhueza, F., Viswanathan, M. R., & Kim, K. (2023). Superparamagnetic and antimicrobial biosynthesis of Ce/NiO nanomaterials for biomedical applications. Nano-Structures & Nano-Objects, 35, 101018. https://doi.org/10.1016/j.nanoso.2023.101018 Khan, I. I. I., Saeed, K., & Khan, I. I. I. (2019). Nanoparticles: Properties, applications and toxicities. Arabian Journal of Chemistry, 12(7), 908–931. https://doi.org/10.1016/j.arabjc.2017.05.011 Khan, Y., Sadia, H., Ali Shah, S.  Z., Khan, M.  N., Shah, A.  A., Ullah, N., Ullah, M.  F., Bibi, H., Bafakeeh, O.  T., Khedher, N.  B., Eldin, S.  M., Fadhl, B.  M., & Khan, M.  I. (2022). Classification, synthetic, and characterization approaches to nanoparticles, and their applications in various fields of nanotechnology: A review. Catalysts, 12(11), 1386. https://doi. org/10.3390/catal12111386 Krkobabić, A., Marković, D., Kovačević, A., Tadić, V., Radoičić, M., Barudžija, T., Ilic-Tomic, T., & Radetić, M. (2022). Antimicrobial nanocomposites based on oxidized cotton fabric and in situ biosynthesized copper oxides nanostructures using bearberry leaves extract. Fibers and Polymers, 23(4), 954–966. https://doi.org/10.1007/s12221-­022-­4639-­5 Li, Y., Lu, Y.-L., Wu, K.-D., Zhang, D.-Z., Debliquy, M., & Zhang, C. (2021). Microwave-assisted hydrothermal synthesis of copper oxide-based gas-sensitive nanostructures. Rare Metals, 40(6), 1477–1493. https://doi.org/10.1007/s12598-­020-­01557-­4 Lyu, J., Long, X., Xie, T., Jiang, G., Jiang, J., Ye, L., & Li, Q. (2021). Copper oxide nanoparticles promote α-synuclein oligomerization and underlying neurotoxicity as a model of Parkinson’s disease. Journal of Molecular Liquids, 323, 115051. https://doi.org/10.1016/j. molliq.2020.115051 Mallakpour, S., Azadi, E., & Hussain, C. M. (2022). Fabrication of air filters with advanced filtration performance for removal of viral aerosols and control the spread of COVID-19. Advances in Colloid and Interface Science, 303, 102653. https://doi.org/10.1016/j.cis.2022.102653 Moschini, E., Colombo, G., Chirico, G., Capitani, G., Dalle-Donne, I., & Mantecca, P. (2023). Biological mechanism of cell oxidative stress and death during short-term exposure to nano CuO. Scientific Reports, 13(1), 2326. https://doi.org/10.1038/s41598-­023-­28958-­6

CuO Nanoparticles for Antimicrobial/Antiviral Applications

117

Naika, H. R., Lingaraju, K., Manjunath, K., Kumar, D., Nagaraju, G., Suresh, D., & Nagabhushana, H. (2015). Green synthesis of CuO nanoparticles using Gloriosa superba L. extract and their antibacterial activity. Journal of Taibah University for Science, 9(1), 7–12. https://doi. org/10.1016/j.jtusci.2014.04.006 Naz, S., Gul, A., & Zia, M. (2020). Toxicity of copper oxide nanoparticles: A review study. IET Nanobiotechnology, 14(1), 1–13. https://doi.org/10.1049/iet-­nbt.2019.0176 Naz, S., Gul, A., Zia, M., & Javed, R. (2023). Synthesis, biomedical applications, and toxicity of CuO nanoparticles. Applied Microbiology and Biotechnology, 107(4), 1039–1061. https://doi. org/10.1007/s00253-­023-­12364-­z Ontiveros-Robles, J.  A., Villanueva-Flores, F., Juarez-Moreno, K., Simakov, A., & Vazquez-­ Duhalt, R. (2023). Antibody-functionalized copper oxide nanoparticles with targeted antibacterial activity. ChemistryOpen, 12(5). https://doi.org/10.1002/open.202200241 Outokesh, M., Hosseinpour, M., Ahmadi, S. J., Mousavand, T., Sadjadi, S., & Soltanian, W. (2011). Hydrothermal synthesis of CuO nanoparticles: Study on effects of operational conditions on yield, purity, and size of the nanoparticles. Industrial & Engineering Chemistry Research, 50(6), 3540–3554. https://doi.org/10.1021/ie1017089 Pandiyarajan, T., Udayabhaskar, R., Vignesh, S., James, R. A., & Karthikeyan, B. (2013). Synthesis and concentration dependent antibacterial activities of CuO nanoflakes. Materials Science and Engineering: C, 33(4), 2020–2024. https://doi.org/10.1016/j.msec.2013.01.021 Paul, W., & Sharma, C.  P. (2010). Inorganic nanoparticles for targeted drug delivery. In Biointegration of medical implant materials (pp.  204–235). Elsevier. https://doi. org/10.1533/9781845699802.2.204 Perelshtein, I., Levi, I., Perkas, N., Pollak, A., & Gedanken, A. (2022). CuO-coated antibacterial and antiviral car air-conditioning filters. ACS Applied Materials & Interfaces, 14(21), 24850–24855. https://doi.org/10.1021/acsami.2c06433 Perlman, O., Weitz, I.  S., & Azhari, H. (2015). Copper oxide nanoparticles as contrast agents for MRI and ultrasound dual-modality imaging. Physics in Medicine and Biology, 60(15), 5767–5783. https://doi.org/10.1088/0031-­9155/60/15/5767 Raghavendra, G.  M. G.  M., Jung, J., Kim, D., Varaprasad, K., & Seo, J. (2016). Identification of silver cubic structures during ultrasonication of chitosan AgNO 3 solution. Carbohydrate Polymers, 152, 558–565. https://doi.org/10.1016/j.carbpol.2016.07.045 Rajendaran, K., Muthuramalingam, R., & Ayyadurai, S. (2019). Green synthesis of Ag-Mo/CuO nanoparticles using Azadirachta indica leaf extracts to study its solar photocatalytic and antimicrobial activities. Materials Science in Semiconductor Processing, 91, 230–238. https://doi. org/10.1016/j.mssp.2018.11.021 Sajjad, H., Sajjad, A., Haya, R. T., Khan, M. M., & Zia, M. (2023). Copper oxide nanoparticles: In vitro and in vivo toxicity, mechanisms of action and factors influencing their toxicology. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 271, 109682. https://doi.org/10.1016/j.cbpc.2023.109682 Singh, A. K. (2023). Nanostructured coatings based on metallic nanoparticles as viral entry inhibitor to combat COVID-19. Sustainable Materials and Technologies, 35, e00544. https://doi. org/10.1016/j.susmat.2022.e00544 Solanki, J. N., Sengupta, R., & Murthy, Z. V. P. (2010). Synthesis of copper sulphide and copper nanoparticles with microemulsion method. Solid State Sciences, 12(9), 1560–1566. https://doi. org/10.1016/j.solidstatesciences.2010.06.021 Sportelli, M. C., Izzi, M., Kukushkina, E. A., Hossain, S. I., Picca, R. A., Ditaranto, N., & Cioffi, N. (2020). Can nanotechnology and materials science help the fight against SARS-CoV-2? Nanomaterials, 10(4), 802. https://doi.org/10.3390/nano10040802 Strober, W. (2015). Trypan blue exclusion test of cell viability. Current Protocols in Immunology, 111(1). https://doi.org/10.1002/0471142735.ima03bs111 Toledo, E., Dim, S., Edri, A., Greenshpan, Y., Ottolenghi, A., Eisner, N., Tzadka, S., Pandey, A., Ben Nun, H., Le Saux, G., Porgador, A., & Schvartzman, M. (2022). Nanocomposite coatings for the prevention of surface contamination by coronavirus. PLoS One, 17(8), e0272307. https://doi.org/10.1371/journal.pone.0272307

118

T. Jayaramudu and V. Kokkarachedu

Varaprasad, K., López, M., Núñez, D., Jayaramudu, T., Sadiku, E. R., Karthikeyan, C., & Oyarzúnc, P. (2020). Antibiotic copper oxide-curcumin nanomaterials for antibacterial applications. Journal of Molecular Liquids, 300, 112353. https://doi.org/10.1016/j.molliq.2019.112353 Vázquez-Vázquez, C., Bañobre-López, M., Mitra, A., López-Quintela, M. A., & Rivas, J. (2009). Synthesis of small atomic copper clusters in microemulsions. Langmuir, 25(14), 8208–8216. https://doi.org/10.1021/la900100w Wu, H.-J., Nagai, H., Douura, T., Ishii, M., Kawakami, H., Nakayama, E. E., Shioda, T., & Sato, M. (2022). Coppers film fabrication on glass substrate by complex reduction method for rapid inactivation of SARS-CoV-2 (COVID-19). Functional Materials Letters, 15(04). https://doi. org/10.1142/S1793604722510316 Zhang, Y., Wang, L., Xu, X., Li, F., & Wu, Q. (2018). Combined systems of different antibiotics with nano-CuO against Escherichia coli and the mechanisms involved. Nanomedicine, 13(3), 339–351. https://doi.org/10.2217/nnm-­2017-­0290 Zhang, W., Li, Z., Luo, R., Guo, Q., Xu, F., Yang, F., Zhang, M., Jia, L., & Yuan, S. (2023). Design of tandem CuO/CNTs composites for enhanced tetracycline degradation and antibacterial activity. Separation and Purification Technology, 306, 122548. https://doi.org/10.1016/j. seppur.2022.122548 Zhou, X. J., Harmer, A. J., Heinig, N. F., & Leung, K. T. (2004). Parametric study on electrochemical deposition of copper nanoparticles on an ultrathin polypyrrole film deposited on a gold film electrode. Langmuir, 20(12), 5109–5113. https://doi.org/10.1021/la0497301 Zuniga, J. M., & Cortes, A. (2020). The role of additive manufacturing and antimicrobial polymers in the COVID-19 pandemic. Expert Review of Medical Devices, 17(6), 477–481. https://doi. org/10.1080/17434440.2020.1756771

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis, Antimicrobial Properties, and Toxicity Considerations B. A. Aderibigbe

Introduction Zinc is an essential trace element that is found in body tissues, including the bone, muscle, brain, and skin (Jiang et al., 2018; Tapiero & Tew, 2003). It is also useful in body metabolism and important in neurogenesis, proteins and nucleic acid synthesis, and hematopoiesis (Jiang et  al., 2018; Mahmoud et  al., 2021). Zinc is also important in protecting biological systems from destruction by free radicals (Tapiero & Tew, 2003; Oteiza, 2012). It also prevents the peroxidation of lipids (Gulbahce-­ Mutlu et al., 2021). It exerts antioxidant effects by stabilizing the structure of the cellular membrane and also maintaining the concentration of metallothionein tissue (Jarosz et al., 2017; Marreiro et al., 2017). It also protects the cell from oxidative stress (Chasapis et al., 2012). The anti-inflammatory activity of zinc results from the formation of IL-1β-induced and reduces the activity of smooth muscle cell nitric oxide synthase (Tapiero & Tew, 2003). Zinc oxide nanoparticles are prepared by chemical and physical strategies, resulting in nanosized particles (Mirzaei and Darroudi 2017; Dutta and Sugumaran 2021; Akbar et al. 2020). The nanosized zinc oxide nanoparticles are non-toxic, biocompatible, exhibit a wide band gap semiconductor, high conductivity, strong luminescence, and good photochemical stability (Gharpure et  al. 2020; Kumar et al. 2013; Dakhlaoui et al. 2009). It also exhibits biological activities, including antibacterial (Sirelkhatim et  al. 2015), antioxidant (Rajeshkumar et  al. 2018), antiviral (Nasrollahzadeh et al. 2022), antiparasitic (Khashan et al. 2020), anticancer (Khashan et  al. 2020; Hassan et  al. 2017), anti-inflammatory (Agarwal et  al 2017, Agarwal & Shanmugam 2020), and also promotes wound healing

B. A. Aderibigbe (*) Department of Chemistry, Alice Campus, University of Fort Hare, Alice, South Africa © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_6

119

120

B. A. Aderibigbe

(Batool et  al. 2021; Ndlovu et  al. 2022). The nanosized range of zinc oxide nanoparticles makes them easily taken up into the biological cellular systems (Patel et al., 2016; Jiang et al., 2018). They exist in different shapes, including rod-shaped, spherical, hexagonal, etc. (Nagarajan & Arumugam Kuppusamy, 2013). Their biological effects are influenced by their shape and size. (Mohamed et al., 2019). This chapter reports an overview of zinc oxide nanoparticles in clinical applications for treating infectious and noninfectious diseases.

Methods of Preparation of Zinc Oxide Nanoparticles Zinc oxide nanoparticles are prepared by different methods, including chemical, biological, and physical methods. The method of preparation influences their biocompatibility, particle size, biological activity, etc. (Agarwal et al., 2017). Chemical methods for the preparation of zinc oxide nanoparticles include solgel method, hydrothermal method, precipitation, and chemical reduction (Bandeira et al., 2020). In the biological preparation of zinc oxide nanoparticles, biological substrates are employed, such as fungi, algae, plants, and bacteria (Bandeira et  al., 2020). The physical methods of preparing zinc oxide nanoparticles include microemulsion, ultrasonic irradiation, microwave-assisted, thermal evaporation, wet chemical, spray pyrolysis, etc. (Agarwal et al., 2017).

Physical and Chemical Methods The physical method involves using high pressure, temperature, and expensive equipment. It also uses toxic chemicals (Gnanasangeetha & SaralaThambavani, 2013). The synthesis of ZnO nanoparticles using the microemulsion method is useful in controlling the size and morphology of the nanoparticles. The product yield is usually low with a narrow size distribution (Pineda-Reyes & Olvera, 2018). Microemulsions are thermodynamically stable and are formed by water, surfactant, and oil (Pineda-Reyes & Olvera, 2018). There are few reports on zinc oxide nanoparticles prepared by microemulsions, and the organic phase and surfactants are human and environmental-friendly (Pineda-Reyes & Olvera, 2018; Wang et al., 2014; Yıldırım & Durucan, 2010; Kumar & Rani, 2013, Sarkar et al., 2011). Zinc oxide nanoparticles are also prepared by microwave method. In comparison with traditional methods, microwave-assisted extraction possessed higher efficiency and smaller solvent volume, making it an important approach for the preparation of zinc oxide nanoparticles. This method is clean, simple, and a quick process and the morphology of the nanoparticles can be controlled (Hasanpoor et al., 2015). There are some reports on the use of microwave-assisted methods for the synthesis of zinc oxide nanoparticles (Song et al., 2021; Azizi et al., 2017). In the sol-gel synthesis of zinc oxide nanoparticles, zinc precursors, including sulphate, nitrate, chloride, etc.

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

121

are used. Chemical stabilizers are also used to control the sizes of the nanoparticles and prevent agglomeration of the particles (Naveed et al., 2017; Shafiee et al., 2021).

Biological Methods Biological methods for the synthesis of zinc oxide nanoparticles involve the use of plants, fungi, bacteria, and algae (Fig. 1) (Bandeira et al., 2020). These methods do not require the use of toxic chemicals. Plant extracts contain phytochemicals that are good reducing and capping agents (Ahmed et al., 2022). Plant extracts are eco-­ friendly and affordable and can lead to large-scale production and the production of nanoparticles that are stable with varied size ranges and shapes (Bandeira et  al., 2020). Some reports have revealed the efficacy of using different plant extracts to prepare zinc oxide nanoparticles (Duraimurugan et  al., 2019; Şahin et  al., 2022; Mbenga et al., 2022). Algae use for ZnO nanoparticle synthesis is limited. Microalgae’s capability to degrade toxic metals, converting them to less toxic forms, makes them useful (Rabecca et al., 2022; Anand et al., 2022). Bacteria have also been used to prepare zinc oxide nanoparticles (Faisal et al., 2022; Jayaseelan et al., 2012). Fungi have also been used to prepare zinc oxide nanoparticles (Alavi & Nokhodchi, 2021; Raliya et al., 2016). Fungus-mediated synthesis of metal-based nanoparticles has some advantages, such as bioaccumulation capability, metal tolerance, rapid growth rate, prevents agglomeration of nanoparticles, etc. (Kadam et al., 2019).

Fig. 1  Biological synthesis of nanoparticles (Ali et al., 2020)

122

B. A. Aderibigbe

Toxicity Effect (a Mechanism) on Living Cells ZnO nanoparticles induce toxic effects on bacterial cells by destroying the bacterial cell walls, followed by the uptake of the nanoparticles into the bacterial cells, hindering energy metabolism. The uptake of the nanoparticles is influenced by their particle sizes, etc. (Roy et al., 2015). ZnO nanoparticles’ effect on cancer cell lines, such as human gingival squamous cell carcinoma, has been reported to trigger apoptotic cell death and mitochondrial oxidative damage. In mammalian cell lines, such as A549, it caused significant cellular damage which was time-dependent, revealing its capability to cause respiratory toxicity (Yang et al., 2012). At lower concentrations, ZnO nanoparticles induce toxic and apoptotic effects on subcutaneous rat adipose-derived mesenchymal stem cells (Orazizadeh et  al., 2015). Yousef et  al. (2019) revealed the hepatotoxic and nephrotoxic effects of ZnO nanoparticles. Sarkar et al. (2014) evaluated the ZnO-NPs cytotoxicity and genotoxicity in human lymphocyte cells. The cytotoxic effect of the nanoparticles on the cells was high at a minimum concentration of 500 μg/ml. DNA damage was also significant at a concentration of 1000 μg/mL.

Antimicrobial Efficacy of Zinc Oxide Nanoparticles The mode of zinc oxide nanoparticles on bacteria is via the destruction of the bacterial cell walls and the formation of reactive oxygen species (ROS) (Mendes et al., 2022; Gudkov et  al., 2021). The generation of ROS results in the inhibition of deoxyribonucleic acid (DNA) replication and protein synthesis (Tiwari et al., 2018). They have been investigated for the treatment of bacterial infections in wounds, eyes, respiratory and urinary systems, sites of tissue transplant, sexually transmitted infections, etc. They are widely explored therapeutics for the treatment of bacterial infections due to their biocompatibility, large surface area, ease of uptake into the cells, and selectivity (Bisht & Rayamajhi Bisht, 2016).

Wound Dressings ZnO nanoparticles have been widely investigated for wound healing. The main challenge with the treatment of wounds is bacterial infections. Bacterial infections in wounds inhibit the accelerated healing process (Caldwell, 2020). The wound-­ healing mechanism is very complex, and a wound that does not heal over a short time is known as a chronic wound which is challenging to treat. Some known factors that contribute to wounds becoming chronic are bacterial infections that induce excessive inflammation characterized by the high amount of pro-inflammatory macrophages, Langerhans cells, proteases, neutrophils, etc. High levels of wound

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

123

protease levels inhibit dermal reconstitution and degrade cytokines, growth factors, and dermal extracellular matrix (ECM) components (Wilkinson & Hardman, 2020). ZnO particle size influences the growth of fibroblast cells and their antimicrobial activity. The increase in the particle sizes of the nanoparticles enhanced the fibroblast cell viability in vitro. However, the antimicrobial activity of the nanoparticles varied with particle size and smaller particle sizes displayed higher antimicrobial activity than the higher particle size (Kaushik et al., 2019). Le et al. covered hydrocolloids with ZnO nanoparticles for the UV-blocking treatment of wounds. In vivo studies in Sprague–Dawley rat models over 10-day treatment revealed improved wound healing characterized by reduced pro-inflammatory cytokines, increasing expression of fibroblast biomarkers, revealing induced proliferation phase of the wound healing (Le et  al., 2022). The efficacy of azithromycin-loaded zinc oxide nanoparticles loaded into hydroxyl propyl methylcellulose-based was investigated. The formulation was effective against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) with enhanced epidermal regeneration, high levels of collagen fiber formation, and promising features for accelerated healing of infected wounds (Saddik et al., 2022) (Fig. 2). Loading heparinized zinc oxide nanoparticles into chitosan-poly(vinyl alcohol) hydrogels enhanced the antibacterial synergistic effect, decreased the deposition of

Fig. 2 (a) Healing images of wounds of rats treated at 1, 3, and 7 days postinfection. (b) Bacterial load burden in the wounded skin at 1, 3, and 7 days postinfection expressed as means ± SD. CFU, colony forming units. (c) The effect of azithromycin, ZnO nanoparticles, and azithromycin-ZnO nanoparticles on the percentage of wound contraction for 10  days after infection (Saddik et al., 2022)

124

B. A. Aderibigbe

collagen, accelerated wound closure, and re-epithelialized full-thickness wounds on Wistar rats (Khorasani et al., 2021). Huang et al. incorporated ZnO nanoparticles into poly(lactide-co-glycolic acid)/silk fibroin nanofibers. The nanofibers were active against E. coli and S. aureus. Facilitated rapid wound closure characterized by collagen deposition, angiogenesis, re-epithelialization, and granulation tissue formation (Huang et  al., 2021). ZnO nanoparticles prepared by green using Lawsonia inermis leaf extract were loaded into carbopol-based gels. In vivo studies on albino rats showed that treatment with the formulation improved skin elasticity, re-epithelialization, collagen deposition, and reduced inflammatory cell infiltration with scarless wound healing (Metwally et al., 2021). ZnO nanoparticles prepared using psyllium gel displayed a rod shape with hexagonal prism-like bases. The nanoparticles were effective against Bacillus subtilis, Bacillus licheniformis, E.coli, and Salmonella shigella. In vivo studies showed that the nanoparticles decrease MMP-1 and MMP-2 levels but increase the mRNA levels of fibronectin and collagen types (I & III) (Azam et al., 2023). ZnO nanoparticles prepared using the root extract of white radish were effective against Escherichia fergusonii and E.coli (Kumar et al., 2019). Hydrothermal method was used to prepare ZnO nanoparticles,  which were ­incorporated into gum acacia-alginate nanocomposites. In vivo studies in full-­ thickness excision wounds on rabbits accelerated wound healing with decreased inflammation without the formation of scar formation (Manuja et al., 2020). A surgical suture was loaded with zinc oxide nanoparticles. The nanoparticles displayed rod shape with an antibacterial effect against Methicillin-resistant staphylococcus aureus (MRSA) and E. coli. In vivo studies by treating the incisions made in Sprague–Dawley rats with the zinc oxide nanoparticle-loaded surgical sutures accelerated epithelialization and contraction of the wound with mild inflammatory effect. The formation of collagen fibers was also enhanced with rapid angiogenesis (Irfan et  al., 2022). ZnO nanocomposite prepared by an ultrasonic method using carboxymethyl chitosan produced spherical shape nanoparticles with an average diameter of 18 nm. The antibacterial activity of the nanocomposites against S. aureus was high together with good hemostatic effect and hemocompatibility. The unique features reveal their potential application in bleeding and infected wounds (Rao et  al., 2020). Poly(vinyl alcohol)-based nanofibers were incorporated with ZnO nanoparticles. The minimum inhibitory concentration of the nanoparticles-loaded nanofibers E. coli and S. aureus was 62.5 and 250 μg/mL, respectively. In vivo studies showed accelerated epithelial regeneration, significant angiogenesis, and rapid wound-healing rate (Norouzi et al., 2021). Rhamnolipid-coated zinc oxide nanoparticles have been reported to be promising wound dressings for treating infected wounds. In vivo studies on a rat model showed that the rhamnolipid-coated zinc oxide nanoparticles were effective against S. aureus on day 5 of the treatment. The nanoparticles decreased wound size, and there was a rapid formation of the epidermis. The nanoparticles were nontoxic on fibroblast cell line L929 and nonhemolytic on blood cells, indicating their promising application as topical wound dressings (Malakar et al., 2023). Electrospun fibers prepared from oxidized sodium alginate were incorporated with zinc oxide

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

125

nanoparticles. Incorporating 2 wt% of the nanoparticles exhibited good antibacterial activity against S. aureus and E. coli with good biocompatibility. The nanoparticle-­loaded nanofibers promoted anti-inflammatory response, epithelialization, and neovascularization in a full-thickness excisional wound defect model in rats (Wang et al., 2023). ZnO nanoparticles prepared using leaf extract of N. sativa were effective against B. cereus, S. aureus, E. coli, and Pseudomonas aeruginosa (P. aeruginosa). The wound-healing percentage was 97% which was more significant than the plant extract (78%) in 4  weeks (Bai & Jarubula, 2023). Carboxymethylcellulose-­ hyaluronic acid gel loaded with zinc oxide nanoparticles displayed good antibacterial and induced cell migration (Paramadini et  al., 2023). The combination of alginate-aloe vera film loaded with ZnO nanoparticles with mupirocin was evaluated as a potential wound dressing for the treatment of wounds caused by delayed cesarean. The clinical studies performed on 800 pregnant women showed reduced redness, oedema, and ecchymosis, with no significant allergic reaction. The wound healing was accelerated in the patients (Hou et al., 2021). ZnO nanoparticles have also been loaded in water-soluble wound dressings with good antibacterial and hemostasis effects (Buyana et al., 2020a, b, Ndlovu et al., 2022).

Ophthalmic Applications The ocular delivery of ZnO nanoparticles has been investigated by some researchers for the treatment of bacterial infections. The eyes are also prone to infections such as keratitis that can contaminate the contact lenses. The incorporation of zinc oxide nanoparticles coated with phytochemicals in combination with gallic acid and tobramycin as a coating to contact lenses. The coated contact lenses exhibited excellent antibacterial and antibiofilm activity against multidrug-resistant bacteria responsible for bacterial keratitis, such as P. aeruginosa, S. aureus, and E. coli. The coated contact lenses were also able to inhibit fungal strains such as Aspergillus fumigatus, Fusarium Solani, and Candida albicans. The coating was cytocompatible with keratinocytes cell lines and the human corneal epithelial cells (Khan et al., 2021). Laser ablation technique was used to prepare spherically shaped zinc oxide nanoparticles with average sizes of 9.8 and 10.2 nm, depending on the laser ablation times. The nanoparticles effectively inhibited ophthalmological bacteria, such as P. aeruginosa and MRSA. The nanoparticles were biocompatible with retinal epithelial cells, ARPE-19, with moderate antioxidant activity (El-Gendy et al., 2022). The wearing of contact lenses can alter the eye environment promoting bacteria growth that affects the health of the eye. Contact lens contamination by microbes causes eye-related conditions and vision loss. The most common microbes associated with contact lens wearing are S. aureus and Streptococcus pneumonia (Datta et al., 2017). Contact lenses were coated with a combination of gallic acid, ZnO nanoparticles, and chitosan. The coating enhanced the antibacterial activity of the contact lenses against S. aureus. The coating was biocompatibility with human cell

126

B. A. Aderibigbe

lines (Hoyo et al., 2019). Shayani et al. used the sol-gel process to synthesize ZnO nanoparticles as contact lens antimicrobial media. The nanoparticles were effective against P. aeruginosa, Candida albicans, Listeria monocytogenes, S. aureus, Bacillus subtilis, Staphylococcus epidermidis, E. coli, and Salmonella typhi (Shayani Rad et al., 2020). Mansur et al. conjugated zinc oxide nanoparticles to a polypyrrole-based polymer to treat free-living amoebae that cause infections in the cornea. Acanthamoeba spp. is responsible for Acanthamoeba keratitis. The polypyrrole-zinc oxide nanoparticles conjugate inhibited the growth of A. castellanii in vitro (Mansur et al., 2022). Strains of bacteria collected from patients suffering from eye infections in Samarra hospitals were Staphylococcus epidermidis, S. aureus, Streptococcus pneumonia, Haemophilus Influenzae, P. aeruginosa, E. coli, and C. albicans. The antibacterial studies using zinc oxide nanoparticles showed that the nanoparticles were effective at concentrations of 100% and 150% in inhibiting S. aureus, E. coli, and C. albicans, respectively (Hammadi et  al., 2022). A study that assessed the inhibitory effect of ZnO-nanoparticles in combination with meropenem against biofilm formation by multidrug-resistant P. aeruginosa strains was reported by El-Telbany et al. In vivo studies on P. aeruginosa-induced keratitis rat model revealed complete healing. The combination promoted a synergistic effect against P. aeruginosa infections, revealing the efficacy of zinc oxide nanoparticles in the treatment of ocular infections (El-Telbany et  al., 2022). Sun et  al. developed a terbium-doped zinc oxide constructed dual-light-responsive nitric oxide (NO)-releasing nanoparticle, which was modified onto the surface of contact lenses. The system released reactive oxygen species and nitric oxide that killed bacteria (P. aeruginosa, E. coli, and MRSA) with a reduced inflammatory response suitable for treating bacterial keratitis (Sun et al., 2023). Chew et al. loaded zinc oxide nanoparticles onto soft contact lenses to inhibit the adhesion of P. aeruginosa and S. aureus. The nanoparticles were compatible with human corneal epithelial cells in vitro (Chew et al., 2022).

Urinary Tract Infections Urinary tract infections occur in any part of the urinary system. Some of the risk factors are female gender (it is more common in women), diabetes, sexual activity, obesity, vaginal infection, etc. (Flores-Mireles et al., 2015). It can either be complicated or not. The complicated urinary tract infections can cause urinary obstruction and retention renal failure and are caused by drainage devices, etc. Urinary tract infections are caused by fungi and Gram-negative and Gram-positive bacteria. The most common causative agent is Escherichia coli. Other microbes that are responsible for urinary tract infection are Staphylococcus saprophyticus, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis, Pseudomonas aeruginosa, Candida spp., and S. aureus (Flores-Mireles et al., 2015).

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

127

Passiflora caerulea fresh leaf extract was used to prepare zinc oxide nanoparticles with an average particle size of 37.67  nm. The nanoparticles were effective against E.coli, Streptococcus sp., Enterococcus sp., and Klebsiella sp. The antibacterial effect was dose-dependent, revealing their potential application for the treatment of urinary tract infections (Santhoshkumar et al., 2017). Hosseini et al. studied the effect of zinc oxide nanoparticles on proteins that initiate adhesion in the filamentous form of C. albicans that causes urinary tract infections. Candida urinary tract infections cultured from 280 women in hospital Sayad Shirazi, in Northeastern, were tested by the disk diffusion method on ZnO nanoparticles with a size range of 20–40  nm diameters. The minimum inhibition concentration (MIC) range of the nanoparticles was 0.05–296  μg/mL and significantly reduced agglutinin-like sequence 1 (ALS1) and agglutin-like sequence 3 (ALS3) gene expression. The nanoparticles inhibited the growth and adhesion of the fluconazole-resistant C. albicans strains of urinary tract infections (Hosseini et al. 2019). Bhande et al. studied the synergistic effect of combining zinc oxide nanoparticles with β-lactam antibiotics on spectrum β-lactamase producers common in urinary tract infections. The zinc oxide nanoparticles were prepared by the solgel method with an average particle size of 15  nm. ZnO nanoparticles were combined with cefotaxime, ceftriaxone, ampicillin, and cefepime and tested on E. coli, K. pneumoniae, S. paucimobilis, and P. aeruginosa. The combination induced membrane leakage which damaged the cell membrane thereby leading to death cell death. The finding reveals that ZnO nanoparticles are potential adjuvant in combination therapy of ceftriaxone, ampicillin, cefotaxime, and cefepime (Bhande et al., 2013). Chandra et al. reported the biosynthesis of zinc oxide nanoparticles from the leaf extract of the plant, Berberis aristata. The nanoparticles displayed good antibacterial activities against S. aureus, E.coli, Klebsiella pneumoniae, Bacillus cereus, Bacillus subtilis, and Serratia marcescens, microbes that cause urinary tract infections (Chandra et al., 2019). Kotb et al. investigated the efficacy of combining fungal metabolite, 6-pentyl α pyrone lactone with zinc oxide nanoparticles on multidrug-resistant Enterobacterales obtained from urinary tract infections. ZnO nanoparticles exerted an excellent antimicrobial effect with MIC values in the range of 0.015–32 μg/mL. The combination of ZnO nanoparticles with 6-pentyl α pyrone lactone induced a greater synergistic effect, revealing the combination as a promising approach to the treatment of urinary tract infections (Kotb et al., 2022). Vasudevan et  al. developed photoluminescence-based biosensors using ZnO nanoparticles, which were prepared via a microwave-assisted process functionalized with cysteamine to diagnose urinary tract infections. It was designed to detect the quorum-sensing signaling molecules of Gram-negative bacteria, N-acyl-­ homoserine lactones involved in bacterial communication. The device exhibited a maximum sensitivity of 97% in the detection of N-acyl-homoserine lactones (Vasudevan et al., 2020). Murugan et al. prepared nanoparticles of zinc oxide from Limonia acidissima. The nanoparticles inhibited microbes responsible for biofilm formation in urinary tract infections, such as Shigella, Salmonella paratyphi, Streptococcus, Staphylococcus, and Klebsiella pneumonia (Murugan et al., 2022). Hosseini et al. investigated the effect of zinc oxide nanoparticle solution prepared

128

B. A. Aderibigbe

by the solgel method on C. albicans adhesion and biofilm formation in the surface catheter. The particle size of ZnO nanoparticles was 30 nm. The nanoparticle effect was significant in reducing fluconazole-resistant C. albicans biofilm, indicating their potential application in the treatment of catheter-related urinary tract infections (Hosseini et al. 2018). Other researchers have also reported the efficacy of zinc oxide nanoparticles in the treatment of urinary tract infections (Torabi, 2017; Hosseinkhani et al., 2011).

Tuberculosis Tuberculosis is caused by the bacterium, Mycobacterium tuberculosis, which attacks the lung. The emergence of extensively drug-resistant and multidrug-­ resistant has made the treatment of tuberculosis challenging. Nanoscale structures/ systems have the potential to inhibit bacteria growth due to their capability to interact with biomolecules and antimicrobial effects. MIC results showed that 1 μg/mL induced an inhibitory effect against extensively drug-resistant M. tuberculosis. The combination of zinc oxide nanoparticles with silver nanoparticles also inhibited multi-resistant M. tuberculosis at concentrations of 8 μg/mL, 16 μg/mL, 32 μg/mL, and 64 μg/mL (Heidary et al., 2019). ZnO nanoparticles prepared from aqueous leaf extract of Canthium dicoccum (L.). with an average size of 33 nm inhibited M. tuberculosis at 25  μg  mL−1 (Mahendra et  al., 2020). Patil et  al. prepared zinc oxide nanoparticles using Limonia acidissima L.  The nanoparticle size range was 12–53 nm. These nanoparticles inhibited the growth of M. tuberculosis at a concentration of 12.5 μg/mL (Patil & Taranath, 2016). Vijayakumar et al. synthesized zinc oxide nanomaterials using leaf extracts of Capparis zeylanica leaf. The average particle size of the nanoparticles was 34 nm, and they were also spherically shaped. The nanoparticles displayed excellent effect against Mycobacterium tuberculosis (Vijayakumar et al., 2020). Jafari et al. investigated the efficacy of combining zinc oxide nanoparticles with silver nanoparticles to eliminate phagocytized H37Rv strain of Mycobacterium tuberculosis. The ratio of the nanoparticles was varied and compared to rifampicin. THP-1 cell lines were infected with different concentrations of H37RvMTB and then treated with different ratios of ZnO and silver nanoparticles. ZnO nanoparticles eliminated 18.7 × 104 CFU ml−1 of the bacteria at a concentration of 0.468 ppm. 0.663 ppm of the combination of 5:5 of both nanoparticles eliminated the bacteria. The ZnO nanoparticles displayed high antitubercular in vitro condition but were toxic at a concentration of 0.468 ppm to the THP-1 and normal lung (MRC-5) cell lines (Jafari et al., 2017). Lin et al. hybridized zinc oxide and selenium nanoparticles to obtain spherical core–shell nanoparticles with an average diameter of 90 nm. The mode of action of the nanoparticles was via disruption of the ATP production, increased intracellular ROS level, and destruction of the bacteria membrane structures. It also inhibited the intracellular growth of M. tuberculosis by increasing the production of nitric oxide

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

129

and promoted apoptosis and autophagy of M. tuberculosis-infected macrophages and inhibited the PI3K/Akt/mTOR signaling pathway (Lin et al., 2023). Jafari studied the antibacterial activity of ZnO and MgO nanoparticles together with their combination against H37Rv M. tuberculosis and multidrug-resistant M. tuberculosis. The minimum inhibition concentrations of MgO and ZnO nanoparticles were 0.195 and 0.468 μg mL−1 against 104 of H37Rv M. tuberculosis, respectively. A minimum inhibition concentration of 0.166 μg mL−1 of both nanoparticles combination inhibited 10−4 of H37Rv M. tuberculosis. Both nanoparticles and their combination were not toxic to Vero cell lines. The combination of both nanoparticles is a good approach to promoting synergistic effects against multidrug-resistant tuberculosis (Jafari, 2021). Krishna et al. prepared ZnO nanoparticles by solution combustion synthesis method using lemon juice as the fuel. The synthesized nanoparticles inhibited Mycobacterium tuberculosis H37Ra strain at concentrations of 12.5 μg/mL. The nanoparticles were also nontoxic to normal mammalian cells (L929, 3T3-L1), and in vivo studies using Swiss albino mice for 14 days did not reveal any toxic effect of the nanoparticles (Krishna et al., 2017). Ellis et al. developed biodegradable multimetallic microparticles loaded with silver and zinc oxide nanoparticles for pulmonary delivery of rifampicin. The uptake of the microparticles by M. tuberculosis-infected THP1 cells was efficient in vitro in the macrophage infection model. The microparticles delivered the drug to infected alveolar macrophages. It also destroyed the membrane and the extracellular bacilli on the exterior face of THP1 macrophages, thereby improving the treatment of tuberculosis (Ellis et al., 2018). Jafari et  al. investigated the antituberculosis effect of combining metal oxide nanoparticles. Silver and zinc oxide nanoparticles were prepared by chemical reduction and chemical deposition in an aqueous solution and were combined in the ratio of 8(ZnO):2(AgO). The minimal inhibitory concentration of the combination against M. tuberculosis was 1/32 of the initial concentration. However, ZnO nanoparticles exhibited potent antibacterial activity of 1/128 of the initial concentration but induced cytotoxic activity, on the THP-1 cells. Mixing both nanoparticles produced a potent antibacterial activity against M. tuberculosis with no cytotoxic effects on THP-1 cells (Jafari et al., 2016).

Other Microbial Infections (Gonorrhea) Gonorrhea is a sexually transmitted disease, and it is caused by the bacterium, Neisseria gonorrhoeae. This bacterium infects the mucous membranes of the reproductive tract—urethra, cervix, fallopian tubes, and uterus in women. It also infects the mucous membranes of the urethra, eye, throat, rectum, and mouth. It is transmitted through sexual contact with the vagina, anus, mouth, and penis of an infected partner. It is also transmitted perinatally during childbirth from mother to baby (CDC Fact sheet April, 2023). It is challenging to treat due to drug resistance (Unemo & Nicholas, 2012). There is only one report on the investigation of zinc

130

B. A. Aderibigbe

oxide nanoparticles for the treatment of gonorrhea. Rajashekara et al. synthesized zinc oxide nanoparticles using leaf extracts of Calotropis gigantea (L.) Dryand. and zinc nitrate hexahydrate. The antibacterial activity of the nanoparticles was studied against Neisseria gonorrhoeae ATCC 49226 and showed a 50% zone of inhibition (Rajashekara et al., 2020).

 pplication of Zinc Oxide Nanoparticles for the Treatment A of Bacterial Infections at the Sites of Implants—Orthopedic, Tissue Transplant Infections, and After Tumor Removal Zinc oxide nanoparticles have been employed in the design of orthopedic-based implants to overcome and treat bacterial infection at the site of implants. Bone scaffolds with good antimicrobial activity can prevent infections. The surface of borosilicate bioglass and chitosan composite scaffolds was modified with zinc oxide nanoparticles. In vitro and in vivo studies showed that the scaffolds have displayed good osteogenic and antibacterial properties (Qiu et  al., 2022). Microorganism adhesion to implant scaffolds resulting in the formation of antibiotic-resistant biofilms is a challenging factor with implants. Nanostructured hydroxyapatite scaffolds were incorporated with varied amounts of zinc oxide nanoparticles by Grenho et al. The scaffolds were implanted into the subcutaneous tissue in rats, and it was effective at reducing the bacterial activity of S. aureus in vitro and in vivo, revealing its capability to inhibit implant-associated infections (Grenho et al., 2015). Lv et al. doped ZnO nanoparticles with Cu2+ and Mn2+ ions at different levels. The nanoparticles exhibited a wurtzite crystal structure and nanorod shape. The metal ion-doped nanoparticles were sensitive to S. aureus with good antimicrobial activity Loading the nanoparticles to hydroxyapatite composites revealed significant antibacterial activity with good biocompatibility and was suitable for implant coating (Lv et al., 2022). Developing implants with both high biosafety and strength is crucial. Titanium-­ based implants have been widely investigated due to their unique features, which are excellent mechanical properties, corrosion resistance, and biocompatibility (Wang et al., 2021a, b). However, the issue of infections associated with the implant is still a challenge, causing postoperative implant infection. Microbial infection is due to the adhesion of the bacteria to the implant surface and the formation of biofilm formation. These bacterial infections can result in the loosening of the implants in situ and also further damage to the soft tissue. Furthermore, bacteria adhesion to the surface of the implant resulting in the formation of a biofilm prevents cell adhesion to the implant surface (Wang et  al. 2021a, b). To enhance the antimicrobial activity of titanium-based implants, zinc oxide nanoparticles have been employed. Abdulkareem et al. investigated the antibiofilm activity of titanium disks coated with zinc oxide nanoparticles for a dental implant. A combination of zinc oxide and hydroxyapatite was deposited to the surface of the disc by electrohydrodynamic

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

131

deposition. In vitro antibiofilm studies were performed with human saliva as an inoculum and grown biofilms on the nanoparticle-coated disc for 96 h. The composite coatings promoted effective antibiofilm activity (Abdulkareem et al., 2015). Yang et al. reported the efficacy of coating titanium-based implants with naringin and Zn nanoparticles after bone tumor resection that resulted in large bony deficits. However, in osteosarcoma resection, titanium implants are prone to bacterial invasion and tumor recurrence. To overcome the aforementioned limitations, naringin and Zn nanoparticles were deposited on the surface of the implant. The release profiles of naringin and zinc nanoparticles promoted increased oxidative stress on the bacteria, E.coli and S. aureus and also on the osteosarcoma cells. The accumulation of ROS destroyed the bacterial membrane and biofilm and also resulted in osteosarcoma cell apoptosis. The findings indicated that coating nanoparticles to the surface of titanium-based implants are effective in overcoming microbial infections and enhancing the reconstruction of large bony after osteosarcoma resection (Yang et al., 2020). Wang et al. coated titanium implants with ZnO nanoparticles, chitosan, and nanocrystal hydroxyapatite. The modification of the surface of the implant with polydopamine provided high adhesion of the deposited zinc oxide nanoparticles and inhibited the growth of E. coli and S. aureus. The further coating of chitosan and nanocrystal hydroxyapatite on the zinc oxide nanoparticles enhanced the cytocompatibility and bone formation capability of implants (Wang et al., 2021a, b). Wen et al. developed ZnO nanoparticle-loaded mesoporous TiO2 coating-based titanium implants by evaporation-induced self-assembly method and one-step spin coating for controlled release of zinc ions over a long-term with reduced cytotoxic effects. The developed systems were effective at overcoming the cytotoxic effect of ZnO nanoparticles with the absence of excess reactive oxygen species and improved bone mesenchymal stem cells adhesion, proliferation, and osteogenic activity. In vivo study was also performed by embedding the implants into the alveolar fossa of Sprague–Dawley rats after tooth extraction. The implants enhanced bone regeneration and osseointegration in vivo. They were also effective against Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans and useful for preventing peri-implantitis of dental implants (Wen et al., 2023). Li et al. dispersed polystyrene-­ acrylic acid-based colloidal templates on titanium implants followed by coating with zinc oxide nanoparticles and silica membrane which were pretreated by 5,5-dimethylhydantoin followed by chlorination. The titanium implant surface exhibited high antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus with no cytotoxic effect on MC3T3-E1 preosteoblast, revealing a self-antibacterial approach for metallic implants without the use of antibiotics (Li et al., 2017). Zhang et al. developed a coating prepared from nanostructured titanium oxide/zinc oxide by micro-arc oxidation followed by hydrothermal treatment for titanium implants to prevent peri-implant infection. The rate of release of zinc ions was reduced with good cytocompatibility and antibacterial activity, features that are crucial for titanium implant coatings (Zhang et al., 2018). Yao et al. deposited irregular and nanorod-shaped ZnO nanoparticles doped into TiO2 nanotubes by electrodeposition. The antibacterial properties of ZnO nanoparticles doped into TiO2 nanotubes on S. aureus were significant due to the release of

132

B. A. Aderibigbe

zinc ions from the nanoparticles and the morphology. Furthermore, the deposition of ZnO nanoparticles into the TiO2 nanotubes reduced the inflammatory reaction of titanium-based implants, an important approach to enhance bioactivity (Yao et al., 2018). Bagchi et  al. used squaraine dye as a photosensitive material, which was covalently attached to the ZnO nanoparticle surface to form nanohybrids. The photoinduced interfacial electron transfer process from the excited state of the dye to the conduction band of nanoparticles generated ROS that provided the antimicrobial action against S. aureus. An artificial medical implant mimicking titanium sheets coated with nanohybrid-induced light-triggered disrupted the adherence property of matured biofilms, a notable feature for the treatment of life-threatening infections and biofilm formation on implants (Bagchi et al., 2018). Other reports on the efficacy of zinc oxide nanoparticles for coating medical implants have revealed significant antibacterial activity against staphylococcal biofilm which was dependent on the pyramid-shaped morphology (McGuffie et  al., 2016), S. aureus and Proteus vulgaris and influenced by the particle size (Mahamuni et al., 2019). β-phase poly(vinylidene fluoride) scaffolds doped with ZnO nanoparticles by electrospinning for orthopedic applications were effective against S. aureus, E.coli, and Methicillin-resistant Staphylococcus aureus (MRSA) (Li et al., 2018). Applerot et al. coated glass slides with zinc oxide nanoparticles to inhibit the formation of biofilm and the bacteria, E. coli and S. aureus due to the generation of hydroxyl radicals. It reveals that nanoparticles of zinc oxide have self-sterilizing properties useful for surface medical implants (Applerot et al., 2012). Pokrowiecki et al. prepared nanoparticles composed of ZnO and Ag by microwave solvothermal synthesis. The nanoparticles were loaded by high-power ultrasonic deposition onto the surface of titanium-healing abutments. The nanoparticles on the surface of the titanium-healing abutments inhibited the formation of biofilm and were effective against S. mutans, S. oralis, S. aureus, and E. coli. This approach is useful to prevent and treat intraoral and extraoral peri-implant infections in the head and neck (Pokrowiecki et al., 2022). Arshad et al. loaded zinc oxide nanoparticles into a bioactive thiolated chitosan-alginate bandage to treat postoperative surgical site infections. The in vitro and in vivo antibacterial activity of the bandage was high with improved tissue generation and accelerated wound healing. It was also effective for treating surgical site infections (Arshad et al., 2019).

Antiviral Therapeutics The antiviral activity of zinc oxide nanoparticles has been evaluated by several researchers. They are easily taken up by biological tissues. They also exhibit good biocompatibility with human cells when compared to zinc metal. Their antiviral activity mode of action against many viruses is by inhibiting viral entry, replication, and spreading to the organs. They also promote the generation of reactive oxygen species causing oxidative injury and viral death (El-Megharbel et al., 2021).

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

133

Herpes and Human immunodeficiency virus Herpes simplex virus type 1 (HSV-1) is an infectious virus, which is transmitted by oral contact. It causes encephalitis in children and adults. Herpes simplex virus type 2 (HSV-2) is sexually transmitted and is closely associated with genital herpes (Looker et  al., 2015). However, HSV-1 can also be transmitted through oral sex (Looker et al., 2015). HSV-2 infection makes the patient prone to acquiring human immunodeficiency virus (HIV) susceptibility although the association is not fully understood (Looker et al., 2015; WHO 5th April 2023). The effects of zinc oxide nanoparticles on HSV-1 have been reported by some researchers. Melk et al. prepared zinc oxide nanoparticles using an alcohol extract of Plumbago indica L. The average particle size was 32.58 nm with a hexagonal shape. The antiviral effect of the zinc oxide nanoparticles against HSV-1 was significant with an IC50 value of 23.17 μg/mL (Melk et al., 2021). The antiviral activity of nanoparticles against HSV-1 can be attributed to an interaction with the virus particles, resulting in the inhibition of HSV replication. Farouk and Sgebi explored zinc oxide nanoparticles as anchoring moieties by preparing oleic acid-modified and chitosan-Zinc nanoparticles. The synthesized nanoparticles were treated with Vero cells before viral infection to evaluate their capability to interact with cellular targets. The nanoparticles inhibited HSV-1 infection, reducing the viral infectivity titer in the range of 7.7–12.9%. Incubating HSV-1 with the synthesized nanoparticles revealed a significant inhibition that was dependent on time with complete inactivation of the virus in 24 h. The surface modification of zinc oxide nanoparticles is effective in neutralizing the virus (Farouk & Sgebl, 2018). Tavakoli et  al. investigated the inhibitory effects of zinc oxide nanoparticles and polyethylene glycol coated with zinc oxide nanoparticles on HSV-1. Polyethylene glycol coated with zinc oxide nanoparticles (200 μg/mL) induced a 2.5 log10 TCID50 reduction in virus titer with an inhibition rate of 92% in copy number of HSV-1 genomic DNA. PEGylation is an effective approach in reducing the cytotoxic effect of the nanoparticles and increasing their antiviral activity (Tavakoli et  al., 2018). ZnO nanoparticles have also been employed in the design of streptavidin-labeled fluorescence nanoparticle-based immunoassay for the detection of HIV infection. Cysteine was grafted to the carboxyl groups on the surface of the nanoparticles with fluorescence at 546 nm when excited at 358 nm. The immunoassay exhibited true results when tested on clinical samples. It was found to be useful in improving blood safety and reducing the antibody-negative window period in blood donors (Avinash Chunduri et al., 2017).

Respiratory Infections (COVID-19 and Influenza) Zinc oxide nanoparticles have been evaluated as therapeutics for the treatment of respiratory infections, such as influenza and COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped RNA virus, and it causes

134

B. A. Aderibigbe

COVID-19, a respiratory infection. A sneeze or cough from persons infected with the SARS-CoV-2 coronavirus produces tiny droplets containing the virus that easily contaminates the surfaces, promoting transmission to other persons. There are reports on self-decontaminating surface materials, a promising approach to preventing the transmission of the disease transmission (Merkl et al., 2021). Merkl et  al. prepared nanocoatings of zinc oxide, silver, and copper oxide by flame aerosol direct deposition that combines the preparation of the nanoparticles and assembly of the nanocoating. The nanocoatings were deposited on flat solid substrates by thermophoresis. The antiviral capacity of the nanocoatings was evaluated against SARS-CoV-2 by plaque assay. The ZnO nanocoating did significantly affect the virus stability over time when compared to silver nanocoating which reduced the viral load to 98% after 120 min (Merkl et al., 2021). El-Megharbel et al. synthesized zinc oxide nanoparticles as a disinfectant nano-spray against SARS-­ CoV-­2. The nanospray displayed high anti-SARS-CoV-2 activity in vitro with a nonsignificant selectivity index (CC50/IC50 ≤ 1). A low concentration of the nanoparticles produced potent antiviral activity of IC50 = 526 ng/mL. However, the nanospray also induced a cytotoxic effect with CC50 = 292.2 ng/mL, revealing the need for further studies on the complexation of zinc oxide nanoparticles with other compounds to reduce its cellular toxicity and further enhance its antiviral activity against SARS-CoV-2 activities (El-Megharbel et  al., 2021). Alqahtani et  al. combined Pelargonium zonale leaf extract and biosynthesized ZnO nanoparticles and evaluated their efficacy against the human corona 229E virus. The antiviral activity of the nanoparticles was significant when combined with the extract. The viral inhibitory impact IC50 was 41.090, 15.939, and 2.028 μg/mL, respectively, for the extract, the nanoparticles, and the combination of the nanoparticles and extract. The combination of the extract and the nanoparticles promoted greater antiviral activity than the nanoparticles and extract individually. The finding reveals that zinc oxide nanoparticles enhanced cell uptake and reduced cell efflux (Alqahtani et al., 2022). Alrabayah et al. synthesized zinc oxide nanoparticles with particle sizes in the range of 3.41–4.86 nm using Cestrum diurnum extract L. leaf extract. The antiviral activity of the ZnO nanoparticles was significant with IC50 of 7.01 and CC50 of 145.77 when compared to the extract with IC50 = 61.15 and CC50 = 145.87 μg/mL against HCOV-229E. However, their combination revealed higher antiviral activity of IC50 = 2.41 and CC50 = 179.23, revealing the synergistic antiviral effect of combining Cestrum diurnum extract with ZnO nanoparticles (Alrabayah et al., 2022). Attia et al. prepared zinc oxide nanoparticles using hesperidin isolated from food waste orange peels. The nanoparticles had a hexagonal shape with an average particle size of 25 nm. The nanoparticles exhibited higher antiviral activity than hesperidin at a low concentration which is attributed to the nanosize and high surface area of zinc oxide nanoparticles. The nanoparticles were also effective against the hepatitis A virus with a percentage of 44.75% (Attia et al., 2021). The efficacy of zinc oxide nanoparticles against H1N1 influenza virus has been reported. Ghaffari et  al. studied the antiviral activity of PEGylated zinc oxide nanoparticles and zinc oxide nanoparticles against H1N1 influenza virus. In vitro studies of PEGylated zinc oxide and zinc oxide nanoparticles on influenza virus at

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

135

Fig. 3  Preparation of polyvinylidene fluoride composite nanofiber-ZnO nanoparticles (Nageh et al., 2022)

high nontoxic concentrations resulted in a significant reduction in virus titer with inhibition rates of 94.6% and 52.2%, respectively. The surface of the PEGylation nanoparticles played a crucial role in improving the antiviral activity against H1N1 influenza virus (Ghaffari et al., 2019). Rabiee et al. synthesized ZnO nanoparticles using Salvia hispanica leave extract. The H1N1 inhibition rate of the nanoparticles was 40% which was low when compared to oseltamivir with an inhibition rate of 90% (Rabiee et al., 2020). Nageh et al. loaded different concentrations of ZnO nanoparticles into polyvinylidene fluoride composite nanofibers (Fig. 3). Antiviral evaluation of the nanoparticles against human adenovirus type-5 via quantitative polymerase chain reaction assay revealed that loading 5% of the nanoparticles into the nanofibers inhibited viral entry and replication making the nanofiber a potential material for the development of antiviral face mask (Nageh et al., 2022).

Other Viral Infections The efficacy of zinc oxide nanoparticles against other viral infections has been studied. Gupta et al. studied the cytostatic and cytotoxic effects of nanoparticles of ZnO against herpes simplex virus and hepatitis C and E viruses. Their capability to suppress herpes simplex virus infection was via binding and entrapment of the virus,

136

B. A. Aderibigbe

resulting in it inhibiting its entrance into the host cell. They were also effective against hepatitis C and E viruses (Gupta et al., 2022). The hepatitis E virus causes acute liver failure and is transmitted through contaminated water or food. Genotype 3 hepatitis E virus is the main cause of chronic infection in immunocompromised patients with a high risk of progressing to liver cirrhosis. It is also a leading cause of chronic liver disease. Genotype 3 HCV is a major cause of liver cirrhosis and hepatocellular carcinoma in developing countries (Gupta et al., 2022). Kumar et al. reported the efficacy of zinc oxide nanoparticles against the chikungunya virus. The nanoparticles were synthesized by the precipitation method. The anti-chikungunya activity was determined by a change in the viral RNA transcripts within 24 h of virus infection by reverse transcription polymerase chain reaction (RT-PCR). A tenfold reduction of the virus occurred when treated with zinc oxide nanoparticles. The results showed the interaction of zinc oxide nanoparticles with the viruses enhanced the antiviral activity (Kumar et al., 2018). Chikungunya virus is an arbovirus transmitted by mosquito vectors that belong to the Togaviridae family. There are no specific drugs for its treatment, and infected patients are treated with nonsteroidal anti-inflammatory drugs and medicines to relieve some of the symptoms, such as fever and aches. Steroids are used occasionally with no significant outcome (Caglioti et al., 2013). Jana et al. studied the efficacy of zinc oxide nanoparticles loaded into chitosan/ benzyloxy-benzaldehyde-based composites against human cytomegalovirus. The nanoparticles-loaded composites exhibited antiviral and low cytotoxic effects. Human cytomegalovirus infection can cause lethal diseases in immunocompromised individuals and is the principal cause of congenital abnormalities and serious ailments in organ transplant recipients. It is treated with antivirals that exhibit suffer from low bioavailability, toxicity, and antiviral resistance (Jana et al., 2022) Almansorri et al. investigated the effects of zinc oxide nanoparticles on molluscum contagiosum virus infection and replication. In vitro studies showed that the ZnO nanoparticles were not toxic at the highest dose and induced an inhibition percentage of 17.8%, 27.3%, 53.3%, 62.5%, and 75.9%, depending on viral load. The fluorescence emission intensity was evaluated for virally infected cells treated with ZnO nanoparticles which revealed a significant decrease when compared to the virus control, indicating a good antiviral effect (Almansorri et al. 2023). Molluscum contagiosum is a viral infection causing lesions on the soles of the feet and the palms of the hands, the lip, conjunctiva, etc. In immunosuppressed patients, molluscum contagiosum is severe (Chen et al., 2013).

Antifungal Therapeutics Fungal infections are challenging to treat (Rossi et al., 2021). Currently, there are not many reports on the development of new antifungal agents. The available antifungal drugs suffer from some limitations, such as poor water solubility, toxic side

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

137

effects, etc. (Soliman, 2017). Many researchers have explored the therapeutic efficacy of zinc oxide nanoparticles as potential antifungal agents. Pillai et al. synthesized zinc oxide nanoparticles using the plant extracts, Brassica oleracea var. Italica, Beta vulgaris, Cinnamomum verum, and Cinnamomum tamala. The nanoparticles were effective against C. albicans and Aspergillus niger. The nanoparticles prepared using Beta vulgaris and Cinnamomum tamala were highly active against A. niger and C. Albicans, respectively (Pillai et al., 2020). Sharma and Ghose reported zinc oxide nanoparticles with particle sizes in the range of 27.6–31.7 nm prepared by a simple homogeneous precipitation method. The nanoparticles were effective against C. albicans which was dose-dependent (Sharma & Ghose, 2015). Jamdagni et  al. synthesized zinc oxide nanoparticles using an aqueous flower extract of Nyctanthes arbor-tristis and zinc acetate dihydrate. The size range of nanoparticles was 12–32 nm. The nanoparticles were active against Aspergillus niger, Penicillium expansum, and Fusarium oxysporum. The lowest MIC value was 16 μg/mL (Jamdagni et al., 2018). Miri et al. prepared zinc oxide nanoparticles using an aqueous extract of Prosopis farcta fruit with a size range of 40–50 nm. They were effective against C. albicans with minimum fungicidal concentration and minimum inhibitory concentration in the range of 128–512 and 32–64 and μg/mL, respectively (Miri et al., 2020). Abomuti et  al. bio-fabricated zinc oxide nanoparticles using an aqueous leaf extract of Salvia officinalis L. The nanoparticles were active against C. albicans isolates by inhibiting the fungal growth with MIC values in the range of 1.95–7.81 μg/ mL. The antifungal mode of action of the nanoparticles was via inhibition of ergosterol biosynthesis and the disruption of bacterial membrane integrity (Abomuti et al., 2021). ZnO nanoparticles with an average particle size of 17.33 nm have also been prepared using Z. nummularia leaf extract with potent antifungal activity against clinical isolate of Candida spp. (Padalia & Chanda, 2017). Yassin et al. evaluated the efficacy of zinc oxide nanoparticles against multidrug-resistant candidal strains. The nanoparticles were prepared using pomegranate peel extract and exhibited an average particle size was 22.84 nm with potent antifungal activity against C. albicans, C. tropicalis, and C. glabrata strains, with zone diameters of 24.18, 26.35, and 20.17 mm, respectively. The combination of the nanoparticles with antifungal drugs, fluconazole, clotrimazole, and nystatin, promoted synergistic antifungal effects against C. albicans. A combination of the nanoparticles with either terbinafine, nystatin, or itraconazole antifungal drugs showed a high antifungal effect against C. glabrata, a multidrug-resistant strain (Yassin et al., 2022). Souza et al. investigated the effect of zinc oxide nanoparticles on Candida parapsilosis, an emerging fungal pathogen that is a significant cause of wound and tissue infections, and in immunocompromised people. The nanoparticles inhibited the fungal growth at a concentration of 15.65 μg/mL with excellent biocompatibility on red blood cells. The particle size of the nanoparticles was in the range of 35–129 nm, depending on the type of polysaccharides used for their preparation (Souza et al., 2020). Djearamane et  al. reported the antifungal properties of zinc oxide

138

B. A. Aderibigbe

nanoparticles against Candida albicans. The accumulation of nanoparticles followed by the alteration of the morphology of C. albicans was observed. The antifungal activity of the nanoparticles against C. albicans was dose-dependent (Djearamane et  al., 2022). Sharma et  al. reported zinc oxide nanoparticles with flower-shaped morphology and significant inhibition against R. necatrix and F. oxysporum clinical strains (Sharma et al., 2023). Other researchers have reported the efficacy of zinc oxide nanoparticles on C. albicans (Yuvaraj et al., 2023; Terea et al., 2023; Dadgar et al., 2021). Candida albicans is responsible for oral or vaginal candidiasis. Oral infections caused by Candida species are known as oral candidiasis and affect the oropharynx of a person with dysfunctions of the adaptive immune system (Mayer et al., 2013).

Conclusion and Future Perspectives The antimicrobial activity of zinc oxide nanoparticles has been widely reported by several researchers. Their antimicrobial activity is influenced by their particle size and method of preparation. It is also dose-dependent. Combining them with known antimicrobials, plant extracts, and other metal-based nanoparticles resulted in an enhanced antimicrobial effect. However, a thorough investigation of the possible toxicity of zinc oxide nanoparticles over long-term usage is lacking but very crucial. Some researchers have reported their toxic effects (Sánchez-López et  al., 2020). Some of the reported toxicities affect the lungs, resulting in pulmonary bronchitis, emphysema, etc. (Sánchez-López et  al., 2020). Hepatotoxicity has also been reported, resulting from oxidative stress, intracellular calcium overload, and mitochondrial damage (Keerthana & Kumar, 2020, Pei et al., 2022). Nephrotoxicity has also been induced by zinc oxide nanoparticles (Khorsandi et al., 2018). The administration of zinc oxide nanoparticles increased the levels of lactate, creatine, taurine, phosphocholine, α-glucose, etc., revealing their capability to cause renal mitochondria and membrane damage (Yan et al., 2012). ZnO nanoparticles have been reported to cause neuro-inflammation together with memory impairment in animals. They also caused memory deficits (Farokhcheh et al., 2021). Most of the reports revealed the antimicrobial effects of zinc oxide nanoparticles without further studies on the possible toxic effects. Some researchers revealed the effect of combining zinc oxide nanoparticles with other bioactive agents, such as geraniol, curcumin, quercetin, arginine, etc. to overcome their toxic side effects (Farokhcheh et al., 2021, Heidai-­ Moghadam et al., 2019, Faddah et al., 2012). Zinc oxide nanoparticles are promising nanotherapeutics with antimicrobial activities that should be explored further. Acknowledgements  The financial assistance of the Govan Mbeki Research and Development Council, University of Fort Hare, Medical Research Council, and National Research Foundation, South Africa, toward this research is hereby acknowledged. The views and opinions expressed in this manuscript are those of the authors and not of MRC or NRF.

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

139

References Abdulkareem, E. H., Memarzadeh, K., Allaker, R. P., Huang, J., Pratten, J., & Spratt, D. (2015). Anti-biofilm activity of zinc oxide and hydroxyapatite nanoparticles as dental implant coating materials. Journal of Dentistry, 43, 1462–1469. Abomuti, M. A., Danish, E. Y., Firoz, A., Hasan, N., & Malik, M. A. (2021). Green synthesis of zinc oxide nanoparticles using salvia officinalis leaf extract and their photocatalytic and antifungal activities. Biology, 10, 1075. Agarwal, H., & Shanmugam, V. (2020). A review on anti-inflammatory activity of green synthesized zinc oxide nanoparticle: Mechanism-based approach. Bioorganic Chemistry, 94, 103423. Agarwal, H., Kumar, S. V., & Rajeshkumar, S. (2017). A review on green synthesis of zinc oxide nanoparticles–An eco-friendly approach. Resource-Efficient Technologies, 3, 406–413. Ahmed, A. A., Rizvi, Z. R., Shahzad, H., & Farrukh, M. A. (2022). Neodymium oxide nanoparticles synthesis using phytochemicals of leaf extracts of different plants as reducing and capping agents: Growth mechanism, optical, structural and catalytic properties. Journal of the Chinese Chemical Society, 69, 462–475. Akbar, S., Tauseef, I., Subhan, F., Sultana, N., Khan, I., Ahmed, U., & Haleem, K. S. (2020). An overview of the plant-mediated synthesis of zinc oxide nanoparticles and their antimicrobial potential. Inorganic and Nano-Metal Chemistry, 50, 257–271. Alavi, M., & Nokhodchi, A. (2021). Synthesis and modification of bio-derived antibacterial Ag and ZnO nanoparticles by plants, fungi, and bacteria. Drug Discovery Today, 26(8), 1953–1962. Ali, M. A., Ahmed, T., Wu, W., Hossain, A., Hafeez, R., Islam Masum, M. M., Wang, Y., An, Q., Sun, G., & Li, B. (2020). Advancements in plant and microbe-based synthesis of metallic nanoparticles and their antimicrobial activity against plant pathogens. Nanomaterials, 10, 1146. Almansorri, A. K., Al-Shirifi, H. M., Al-Musawi, S. M., & Ahmed, B. B. (2023). A novel application of zinc oxide nanoparticles for inhibition of molluscum contagiosum virus infection. Archives of Razi Institute, 78, 277–285. Alqahtani, A. A., El Raey, M. A., Abdelsalam, E., Ibrahim, A. M., Alqahtani, O., Torky, Z. A., & Attia, H.  G. (2022). The biosynthesized zinc oxide nanoparticles’ antiviral activity in combination with Pelargonium zonale extract against the Human Corona 229E virus. Molecules, 27, 8362. Alrabayah, I. N., Elhawary, S. S., Kandil, Z. A., El-Kadder, E. M. A., Moemen, Y. S., Saleh, A. M., & El Raey, M. A. (2022). Green synthesized zinc oxide nanoparticles based on Cestrum diurnum L. of potential antiviral activity against Human Corona 229-E virus. Molecules, 28, 266. Anand, K. V., Mahalakshmi, D., Selvan, S. M., Ravi, M., Kannan, M., Govindaraju, K., & Shalan, A. E. (2022). Biomass extract of green macroalga Halimeda opuntia assisted ZnO nanoparticles: Preparation, physico-chemical characterization, and antibacterial activity against Vibrio harveyi. Biomass Conversion and Biorefinery, 1–9. Applerot, G., Lellouche, J., Perkas, N., Nitzan, Y., Gedanken, A., & Banin, E. (2012). ZnO nanoparticle-coated surfaces inhibit bacterial biofilm formation and increase antibiotic susceptibility. RSC Advances, 2, 2314–2321. Arshad, R., Sohail, M. F., Sarwar, H. S., Saeed, H., Ali, I., Akhtar, S., Hussain, S. Z., Afzal, I., Jahan, S., & Shahnaz, G. (2019). ZnO-NPs embedded biodegradable thiolated bandage for postoperative surgical site infection: In vitro and in vivo evaluation. PLoS One, 14, e0217079. Attia, G. H., Moemen, Y. S., Youns, M., Ibrahim, A. M., Abdou, R., & El Raey, M. A. (2021). Antiviral zinc oxide nanoparticles mediated by hesperidin and in silico comparison study between antiviral phenolics as anti-SARS-CoV-2. Colloids and Surfaces B: Biointerfaces, 203, 111724. Avinash Chunduri, L. A., Kurdekar, A., Eswarappa Pradeep, B., Kumar Haleyurgirisetty, M., & Hewlett, K. I. (2017). Streptavidin conjugated ZnO nanoparticles for early detection of HIV infection. Advanced Materials Letters, 8, 472–480.

140

B. A. Aderibigbe

Azam, A., Muhammad, G., Aslam, M. S., Iqbal, M. M., Raza, M. A., Akhtar, N., Hussain, M. A., Sajjad, N., Syed, A., Bahkali, A. H., & Shafiq, Z. (2023). Enhanced bactericidal and in vivo wound healing potential of biosynthesized zinc oxide nanoparticles from psyllium mucilage. Applied Organometallic Chemistry, 37, e6923. Azizi, S., Mohamad, R., & Mahdavi Shahri, M. (2017). Green microwave-assisted combustion synthesis of zinc oxide nanoparticles with Citrullus colocynthis (L.) Schrad: Characterization and biomedical applications. Molecules, 22, 301. Bagchi, D., Rathnam, V. S., Lemmens, P., Banerjee, I., & Pal, S. K. (2018). NIR-light-active ZnO-­ based nanohybrids for bacterial biofilm treatment. ACS Omega, 3, 10877–10885. Bai, X., & Jarubula, R. (2023). Development of novel green synthesized Zinc oxide nanoparticles with antibacterial activity and effect on diabetic wound healing process of excisional skin wounds in nursing care during sports training (p.  110453). Inorganic Chemistry Communications. Bandeira, M., Giovanela, M., Roesch-Ely, M., Devine, D. M., & da Silva Crespo, J. (2020). Green synthesis of zinc oxide nanoparticles: A review of the synthesis methodology and mechanism of formation. Sustainable Chemistry and Pharmacy, 15, 100223. Batool, M., Khurshid, S., Qureshi, Z., & Daoush, W. M. (2021). Adsorption, antimicrobial and wound healing activities of biosynthesised zinc oxide nanoparticles. Chemical Papers, 75, 893–907. Bhande, R. M., Khobragade, C. N., Mane, R. S., & Bhande, S. (2013). Enhanced synergism of antibiotics with zinc oxide nanoparticles against extended spectrum β-lactamase producers implicated in urinary tract infections. Journal of Nanoparticle Research, 15, 1–13. Bisht, G., & Rayamajhi, S. (2016). ZnO nanoparticles: A promising anticancer agent. Nano, 3, 3–9. Buyana, B., Aderibigbe, B.  A., Ndinteh, D.  T., Fonkui, Y.  T., & Kumar, P. (2020a). Alginate-­ pluronic topical gels loaded with thymol, norfloxacin and ZnO nanoparticles as potential wound dressings. Journal of Drug Delivery Science and Technology, 60, 101960. Buyana, B., Aderibigbe, B. A., Ray, S. S., Ndinteh, D. T., & Fonkui, Y. T. (2020b). Development, characterization, and in vitro evaluation of water soluble poloxamer/pluronic-mastic gum-gum acacia-based wound dressing. Journal of Applied Polymer Science, 137, 48728. Caglioti, C., Lalle, E., Castilletti, C., Carletti, F., Capobianchi, M.  R., & Bordi, L. (2013). Chikungunya virus infection: An overview. New Microbiology, 36, 211–227. Caldwell, M.  D. (2020). Bacteria and antibiotics in wound healing. Surgical Clinics, 100(4), 757–776. Chandra, H., Patel, D., Kumari, P., Jangwan, J. S., & Yadav, S. (2019). Phyto-mediated synthesis of zinc oxide nanoparticles of Berberis aristata: Characterization, antioxidant activity and antibacterial activity with special reference to urinary tract pathogens. Materials Science and Engineering: C, 102, 212–220. Chasapis, C.  T., Loutsidou, A.  C., Spiliopoulou, C.  A., & Stefanidou, M.  E. (2012). Zinc and human health: An update. Archives of Toxicology, 86, 521–534. Chen, X., Anstey, A.  V., & Bugert, J.  J. (2013). Molluscum contagiosum virus infection. The Lancet Infectious Diseases, 13, 877–888. Chew, J., Tong, T., Chua, M. L., Mungroo, M. R., Yap, Y. X., Misran, M., & Gew, L. T. (2022). The antibacterial activity of zinc oxide nanoparticle-loaded soft contact lens. Current Chemical Biology, 16, 138–144. Dadgar, K., Shadan, L., Moazeni, M., Biparva, P., Yazdani Charati, J., Ebrahimi, Z., & Aryana, M. (2021). In vitro analysis of antifungal effects of acrylic resin modified by zinc oxide nanoparticles on Candida albicans. Journal of Mazandaran University of Medical Sciences, 31, 28–38. Dakhlaoui, A., Jendoubi, M., Smiri, L.  S., Kanaev, A., & Jouini, N. (2009). Synthesis, characterization and optical properties of ZnO nanoparticles with controlled size and morphology. Journal of Crystal Growth, 311, 3989–3996.x. Datta, A., Stapleton, F., & Willcox, M. D. (2017). Bacterial coaggregation among the most commonly isolated bacteria from contact lens cases. Investigative Ophthalmology & Visual Science, 58, 50–58.

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

141

Djearamane, S., Xiu, L. J., Wong, L. S., Rajamani, R., Bharathi, D., Kayarohanam, S., De Cruz, A. E., Tey, L. H., Janakiraman, A. K., Aminuzzaman, M., & Selvaraj, S. (2022). Antifungal properties of zinc oxide nanoparticles on Candida albicans. Coatings, 12, 1864. Duraimurugan, J., Kumar, G. S., Maadeswaran, P., Shanavas, S., Anbarasan, P. M., & Vasudevan, V. (2019). Structural, optical and photocatlytic properties of zinc oxide nanoparticles obtained by simple plant extract mediated synthesis. Journal of Materials Science: Materials in Electronics, 30, 1927–1935. Dutta, G., & Sugumaran, A. (2021). Bioengineered zinc oxide nanoparticles: Chemical, green, biological fabrication methods and its potential biomedical applications. Journal of Drug Delivery Science and Technology, 66, 102853. El-Gendy, A. O., Nawaf, K. T., Ahmed, E., Samir, A., Hamblin, M. R., Hassan, M., & Mohamed, T. (2022). Preparation of zinc oxide nanoparticles using laser-ablation technique: Retinal epithelial cell (ARPE-19) biocompatibility and antimicrobial activity when activated with femtosecond laser. Journal of Photochemistry and Photobiology B: Biology, 234, 112540. Ellis, T., Chiappi, M., Garcia-Trenco, A., Al-Ejji, M., Sarkar, S., Georgiou, T. K., Shaffer, M. S., Tetley, T.  D., Schwander, S., Ryan, M.  P., & Porter, A.  E. (2018). Multimetallic microparticles increase the potency of rifampicin against intracellular Mycobacterium tuberculosis. ACS Nano, 12, 5228–5240. El-Megharbel, S. M., Alsawat, M., Al-Salmi, F. A., & Hamza, R. Z. (2021). Utilizing of (zinc oxide nano-spray) for disinfection against “SARS-CoV-2” and testing its biological effectiveness on some biochemical parameters during (COVID-19 pandemic)—“ZnO nanoparticles have antiviral activity against (SARS-CoV-2)”. Coatings, 11, 388. El-Telbany, M., Mohamed, A.  A., Yahya, G., Abdelghafar, A., Abdel-Halim, M.  S., Saber, S., Alfaleh, M.  A., Mohamed, A.  H., Abdelrahman, F., Fathey, H.  A., & Ali, G.  H. (2022). Combination of meropenem and zinc oxide nanoparticles; Antimicrobial synergism, exaggerated antibiofilm activity, and efficient therapeutic strategy against bacterial keratitis. Antibiotics, 11, 1374. Faddah, L. M., Baky, N. A. A., Al-Rasheed, N. M., Al-Rasheed, N. M., Fatani, A. J., & Atteya, M. (2012). Role of quercetin and arginine in ameliorating nano zinc oxide-induced nephrotoxicity in rats. BMC Complementary and Alternative Medicine, 12, 1–14. Faisal, S., Rizwan, M., Ullah, R., Alotaibi, A., Khattak, A., Bibi, N., & Idrees, M. (2022). Paraclostridium benzoelyticum bacterium-mediated zinc oxide nanoparticles and their in vivo multiple biological applications. Oxidative Medicine and Cellular Longevity, 2022, 1–15. Farokhcheh, M., Hejazian, L., Akbarnejad, Z., Pourabdolhossein, F., Hosseini, S.  M., Mehraei, T.  M., & Soltanpour, N. (2021). Geraniol improved memory impairment and neurotoxicity induced by zinc oxide nanoparticles in male wistar rats through its antioxidant effect. Life Sciences, 282, 119823. Farouk, F., & Sgebl, R. I. (2018). Comparing surface chemical modifications of zinc oxide nanoparticles for modulating their antiviral activity against herpes simplex virus type-1. International Journal of Nanoparticles and Nanotechnology, 4, 21. Flores-Mireles, A. L., Walker, J. N., Caparon, M., & Hultgren, S. J. (2015). Urinary tract infections: Epidemiology, mechanisms of infection and treatment options. Nature Reviews Microbiology, 13, 269–284. Ghaffari, H., Tavakoli, A., Moradi, A., Tabarraei, A., Bokharaei-Salim, F., Zahmatkeshan, M., Farahmand, M., Javanmard, D., Kiani, S.  J., Esghaei, M., & Pirhajati-Mahabadi, V. (2019). Inhibition of H1N1 influenza virus infection by zinc oxide nanoparticles: Another emerging application of nanomedicine. Journal of Biomedical Science, 26, 1–10. Gharpure, S., & Ankamwar, B. (2020). Synthesis and antimicrobial properties of zinc oxide nanoparticles. Journal of Nanoscience and Nanotechnology, 20, 5977–5996. Gnanasangeetha, D., & SaralaThambavani, D. (2013). One pot synthesis of zinc oxide nanoparticles via chemical and green method. Research Journal of Material Science, 2320, 1–81. Gonorrhea: CDC detailed fact sheet. (2023). https://www.cdc.gov/std/gonorrhea/stdfact-­gonorrhea-­ detailed.htm#:~:text=What%20is%20gonorrhea%3F,urethra%20in%20women%20and%20 men. Accessed 15th April 2023.

142

B. A. Aderibigbe

Grenho, L., Salgado, C. L., Fernandes, M. H., Monteiro, F. J., & Ferraz, M. P. (2015). Antibacterial activity and biocompatibility of three-dimensional nanostructured porous granules of hydroxyapatite and zinc oxide nanoparticles—An in vitro and in vivo study. Nanotechnology, 26, 315101. Gudkov, S. V., Burmistrov, D. E., Serov, D. A., Rebezov, M. B., Semenova, A. A., & Lisitsyn, A.  B. (2021). A mini review of antibacterial properties of ZnO nanoparticles. Frontiers in Physics, 9, 641481. Gulbahce-Mutlu, E., Baltaci, S.  B., Menevse, E., Mogulkoc, R., & Baltaci, A.  K. (2021). The effect of zinc and melatonin administration on lipid peroxidation, IL-6 levels, and element metabolism in DMBA-induced breast cancer in rats. Biological Trace Element Research, 199, 1044–1051. Gupta, J., Irfan, M., Ramgir, N., Muthe, K. P., Debnath, A. K., Ansari, S., Gandhi, J., Ranjith-­ Kumar, C. T., & Surjit, M. (2022). Antiviral activity of zinc oxide nanoparticles and tetrapods against the Hepatitis E and Hepatitis C viruses. Frontiers in Microbiology, 13, 1–14. Hammadi, S.  Y., Mahmood, A.  E., Attea, A.  A., Al-Douri, W.  K., Hamdoun, R.  M., & Saleh, N.  S. (2022). Detection of the inhibition activity of alcoholic extract of green tea leaves (Camellia sinensis) and zinc oxide nanoparticles against few bacteria and fungi species isolated from eyes infection. International Journal of Drug Delivery Technology, 12, 1814–1819. Hasanpoor, M., Aliofkhazraei, M., & Delavari, H. J. P. M. S. (2015). Microwave-assisted synthesis of zinc oxide nanoparticles. Procedia Materials Science, 11, 320–325. Hassan, H. F. H., Mansour, A. M., Abo-Youssef, A. M. H., Elsadek, B. E., & Messiha, B. A. S. (2017). Zinc oxide nanoparticles as a novel anticancer approach; in vitro and in vivo evidence. Clinical and Experimental Pharmacology and Physiology, 44, 235–243. Heidai-Moghadam, A., Khorsandi, L., & Jozi, Z. (2019). Curcumin attenuates nephrotoxicity induced by zinc oxide nanoparticles in rats. Environmental Science and Pollution Research, 26, 179–187. Heidary, M., Zaker Bostanabad, S., Amini, S. M., Jafari, A., Ghalami Nobar, M., Ghodousi, A., Kamalzadeh, M., & Darban-Sarokhalil, D. (2019). The anti-mycobacterial activity of Ag, ZnO, and Ag-ZnO nanoparticles against MDR-and XDR-Mycobacterium tuberculosis. Infection and Drug Resistance, 3425–3435. Herpes simplex virus (WHO Key Facts). (2023). https://www.who.int/news-­room/fact-­sheets/ detail/herpes-­simplex-­virus. Accessed 17th April 2023. Hosseini, S. S., Ghaemi, E., & Koohsar, F. (2018). Influence of ZnO nanoparticles on Candida albicans isolates biofilm formed on the urinary catheter. Iranian Journal of Microbiology, 10, 424–432. Hosseini, S. S., Ghaemi, E., Noroozi, A., & Niknejad, F. (2019). Zinc oxide nanoparticles inhibition of initial adhesion and ALS1 and ALS3 gene expression in Candida albicans strains from urinary tract infections. Mycopathologia, 184, 261–271. Hosseinkhani, P., Zand, A. M., Imani, S., Rezayi, M., & Rezaei, Z. S. (2011). Determining the antibacterial effect of ZnO nanoparticle against the pathogenic bacterium, Shigella dysenteriae (type 1). International Journal of Nano Dimension, 1, 279–285. Hou, Y., Gao, Y., Wang, X., Zhang, Y., Li, J., Zhang, H., & Li, X. (2021). Alginate-aloe vera film contains zinc oxide nanoparticles with high degradability and biocompatibility on post-­ cesarean wounds. Journal of Drug Delivery Science and Technology, 66, 102631. Hoyo, J., Ivanova, K., Guaus, E., & Tzanov, T. (2019). Multifunctional ZnO NPs-chitosan-gallic acid hybrid nanocoating to overcome contact lenses associated conditions and discomfort. Journal of Colloid and Interface Science, 543, 114–121. Huang, K., Jinzhong, Z., Zhu, T., Morsi, Y., Aldalbahi, A., El-Newehy, M., Yan, X., & Mo, X. (2021). Exploration of the antibacterial and wound healing potential of a PLGA/silk fibroin based electrospun membrane loaded with zinc oxide nanoparticles. Journal of Materials Chemistry B, 9, 1452–1465. Irfan, M., Munir, H., & Ismail, H. (2022). Characterization and fabrication of zinc oxide nanoparticles by gum Acacia modesta through green chemistry and impregnation on surgical sutures to boost up the wound healing process. International Journal of Biological Macromolecules, 204, 466–475.

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

143

Jafari, A. (2021). Evaluation of magnesium oxide and zinc oxide nanoparticles against multi-drug-­ resistance mycobacterium tuberculosis. Indian Journal of Tuberculosis, 68, 195–200. Jafari, A. R., Mosavi, T., Mosavari, N., Majid, A., Movahedzade, F., Tebyaniyan, M., Kamalzadeh, M., Dehgan, M., Jafari, S., & Arastoo, S. (2016). Mixed metal oxide nanoparticles inhibit growth of Mycobacterium tuberculosis into THP-1 cells. International Journal of Mycobacteriology, 5, S181–S183. Jafari, A., Mosavari, N., Movahedzadeh, F., Nodooshan, S. J., Safarkar, R., Moro, R., Kamalzadeh, M., Majidpour, A., Boustanshenas, M., & Mosavi, T. (2017). Bactericidal impact of Ag, ZnO and mixed AgZnO colloidal nanoparticles on H37Rv Mycobacterium tuberculosis phagocytized by THP-1 cell lines. Microbial Pathogenesis, 110, 335–344. Jamdagni, P., Khatri, P., & Rana, J. S. (2018). Green synthesis of zinc oxide nanoparticles using flower extract of Nyctanthes arbor-tristis and their antifungal activity. Journal of King Saud University-Science, 30, 168–175. Jana, B., Chatterjee, A., Roy, D., Ghorai, S., Pan, D., Pramanik, S. K., Chakraborty, N., & Ganguly, J. (2022). Chitosan/benzyloxy-benzaldehyde modified ZnO nano template having optimized and distinct antiviral potency to human cytomegalovirus. Carbohydrate Polymers, 278, 118965. Jarosz, M., Olbert, M., Wyszogrodzka, G., Młyniec, K., & Librowski, T. (2017). Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling. Inflammopharmacology, 25, 11–24. Jayaseelan, C., Rahuman, A.  A., Kirthi, A.  V., Marimuthu, S., Santhoshkumar, T., Bagavan, A., Gaurav, K., Karthik, L., & Rao, K. B. (2012). Novel microbial route to synthesize ZnO nanoparticles using Aeromonas hydrophila and their activity against pathogenic bacteria and fungi. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 90, 78–84. Jiang, J., Pi, J., & Cai, J. (2018). The advancing of zinc oxide nanoparticles for biomedical applications. Bioinorganic Chemistry and Applications, 2018, 1–18. Kadam, V. V., Ettiyappan, J. P., & Balakrishnan, R. M. (2019). Mechanistic insight into the endophytic fungus mediated synthesis of protein capped ZnO nanoparticles. Materials Science and Engineering: B, 243, 214–221. Kaushik, M., Niranjan, R., Thangam, R., Madhan, B., Pandiyarasan, V., Ramachandran, C., Oh, D. H., & Venkatasubbu, G. D. (2019). Investigations on the antimicrobial activity and wound healing potential of ZnO nanoparticles. Applied Surface Science, 479, 1169–1177. Keerthana, S., & Kumar, A. (2020). Potential risks and benefits of zinc oxide nanoparticles: A systematic review. Critical Reviews in Toxicology, 50, 47–71. Khan, S. A., Shahid, S., Mahmood, T., & Lee, C. S. (2021). Contact lenses coated with hybrid multifunctional ternary nanocoatings (Phytomolecule-coated ZnO nanoparticles: Gallic Acid: Tobramycin) for the treatment of bacterial and fungal keratitis. Acta Biomaterialia, 128, 262–276. Khashan, K. S., Sulaiman, G. M., Hussain, S. A., Marzoog, T. R., & Jabir, M. S. (2020). Synthesis, characterization and evaluation of anti-bacterial, anti-parasitic and anti-cancer activities of aluminum-doped zinc oxide nanoparticles. Journal of Inorganic and Organometallic Polymers and Materials, 30, 3677–3693. Khorasani, M.  T., Joorabloo, A., Adeli, H., Milan, P.  B., & Amoupour, M. (2021). Enhanced antimicrobial and full-thickness wound healing efficiency of hydrogels loaded with heparinized ZnO nanoparticles: In vitro and in vivo evaluation. International Journal of Biological Macromolecules, 166, 200–212. Khorsandi, L., Heidari-Moghadam, A., & Jozi, Z. (2018). Nephrotoxic effects of low-dose zinc oxide nanoparticles in rats. Journal of Nephropathology, 7, 158–165. Kotb, A.  M., Abd El-Aziz, N.  K., Elariny, E.  Y., Yahya, R., Alkhalifah, D.  H. M., & Ahmed, R. M. (2022). Synergistic antibacterial potential of 6-pentyl-α-pyrone lactone and zinc oxide nanoparticles against multidrug-resistant Enterobacterales isolated from urinary tract infections in humans. Antibiotics, 11(4), 440. Krishna, P. G., Ananthaswamy, P. P., Trivedi, P., Chaturvedi, V., Mutta, N. B., Sannaiah, A., Erra, A., & Yadavalli, T. (2017). Antitubercular activity of ZnO nanoparticles prepared by solution combustion synthesis using lemon juice as bio-fuel. Materials Science and Engineering: C, 75, 1026–1033.

144

B. A. Aderibigbe

Kumar, H., & Rani, R. (2013). Structural and optical characterization of ZnO nanoparticles synthesized by microemulsion route. International Letters of Chemistry, Physics and Astronomy, 14, 26–36. Kumar, S. S., Venkateswarlu, P., Rao, V. R., & Rao, G. N. (2013). Synthesis, characterization and optical properties of zinc oxide nanoparticles. International Nano Letters, 3, 1–6. Kumar, R., Sahoo, G., Pandey, K., Nayak, M.  K., Topno, R., Rabidas, V., & Das, P. (2018). Virostatic potential of zinc oxide (ZnO) nanoparticles on capsid protein of cytoplasmic side of chikungunya virus. International Journal of Infectious Diseases, 73, 368. Kumar, A.  K., Saila, E.  S., Narang, P., Aishwarya, M., Raina, R., Gautam, M., & Shankar, E.  G. (2019). Biofunctionalization and biological synthesis of the ZnO nanoparticles: The effect of Raphanus sativus (white radish) root extract on antimicrobial activity against MDR strain for wound healing applications. Inorganic Chemistry Communications, 100, 101–106. Le, V. A. T., Trinh, T. X., Chien, P. N., Giang, N. N., Zhang, X. R., Nam, S. Y., & Heo, C. Y. (2022). Evaluation of the performance of a ZnO-nanoparticle-coated hydrocolloid patch in wound healing. Polymers, 14(5), 1–16. Li, Y., Liu, X., Tan, L., Cui, Z., Yang, X., Yeung, K. W. K., Pan, H., & Wu, S. (2017). Construction of N-halamine labeled silica/zinc oxide hybrid nanoparticles for enhancing antibacterial ability of Ti implants. Materials Science and Engineering: C, 76, 50–58. Li, Y., Sun, L., & Webster, T. J. (2018). The investigation of ZnO/poly (vinylidene fluoride) nanocomposites with improved mechanical, piezoelectric, and antimicrobial properties for orthopedic applications. Journal of Biomedical Nanotechnology, 14, 536–545. Lin, W., Fan, S., Liao, K., Huang, Y., Cong, Y., Zhang, J., Jin, H., Zhao, Y., Ruan, Y., Lu, H., & Yang, F. (2023). Engineering zinc oxide hybrid selenium nanoparticles for synergetic anti-­ tuberculosis treatment by combining Mycobacterium tuberculosis killings and host cell immunological inhibition. Frontiers in Cellular and Infection Microbiology, 12, 1988. Looker, K. J., Magaret, A. S., May, M. T., Turner, K. M., Vickerman, P., Gottlieb, S. L., & Newman, L. M. (2015). Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS One, 10, e0140765. Lv, Y., Song, X., Lei, T., & Yin, P. (2022). Structural and antibacterial properties of doped zinc oxide and their composites with hydroxyapatite. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 651, 129706. Mahamuni, P. P., Patil, P. M., Dhanavade, M. J., Badiger, M. V., Shadija, P. G., Lokhande, A. C., & Bohara, R. A. (2019). Synthesis and characterization of zinc oxide nanoparticles by using polyol chemistry for their antimicrobial and antibiofilm activity. Biochemistry and Biophysics Reports, 17, 71–80. Mahendra, C., Chandra, M. N., Murali, M., Abhilash, M. R., Singh, S. B., Satish, S., & Sudarshana, M. S. (2020). Phyto-fabricated ZnO nanoparticles from Canthium dicoccum (L.) for antimicrobial, anti-tuberculosis and antioxidant activity. Process Biochemistry, 89, 220–226. Mahmoud, M.  A., Yahia, D., Abdel-Magiud, D.  S., Darwish, M.  H., Abd-Elkareem, M., & Mahmoud, U. T. (2021). Broiler welfare is preserved by long-term low-dose oral exposure to zinc oxide nanoparticles: Preliminary study. Nanotoxicology, 15, 605–620. Malakar, C., Kashyap, B., Kalita, M.  C., & Deka, S. (2023). Wound healing efficacy of rhamnolipid-­coated zinc oxide nanoparticle along with its in vivo antibacterial efficacy against Staphylococcus aureus. Experimental Dermatology, 32, 154–164. Mansur, F.  A., Sridewi, N., Anwar, A., Anwar, A., & Shahabuddin, S. (2022). Polypyrrole-­ conjugated zinc oxide nanoparticle as antiamoebic drugs against Acanthamoeba castellanii. Materials Today: Proceedings, 62, 7077–7081. Manuja, A., Raguvaran, R., Kumar, B., Kalia, A., & Tripathi, B. N. (2020). Accelerated healing of full thickness excised skin wound in rabbits using single application of alginate/acacia based nanocomposites of ZnO nanoparticles. International Journal of Biological Macromolecules, 155, 823–833. Marreiro, D. D. N., Cruz, K. J. C., Morais, J. B. S., Beserra, J. B., Severo, J. S., & De Oliveira, A. R. S. (2017). Zinc and oxidative stress: Current mechanisms. Antioxidants, 6, 24.

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

145

Mayer, F.  L., Wilson, D., & Hube, B. (2013). Candida albicans pathogenicity mechanisms. Virulence, 4, 119–128. Mbenga, Y., Mthiyane, M.  N., Botha, T.  L., Horn, S., Pieters, R., Wepener, V., & Onwudiwe, D. C. (2022). Nanoarchitectonics of ZnO nanoparticles mediated by extract of tulbaghia violacea and their cytotoxicity evaluation. Journal of Inorganic and Organometallic Polymers and Materials, 32, 3249–3259. McGuffie, M. J., Hong, J., Bahng, J. H., Glynos, E., Green, P. F., Kotov, N. A., Younger, J. G., & VanEpps, J. S. (2016). Zinc oxide nanoparticle suspensions and layer-by-layer coatings inhibit staphylococcal growth. Nanomedicine: Nanotechnology, Biology and Medicine, 12, 33–42. Melk, M. M., El-Hawary, S. S., Melek, F. R., Saleh, D. O., Ali, O. M., El Raey, M. A., & Selim, N.  M. (2021). Antiviral activity of zinc oxide nanoparticles mediated by plumbago indica L. Extract against herpes simplex virus type 1 (HSV-1). International Journal of Nanomedicine, 16, 8221. Mendes, C. R., Dilarri, G., Forsan, C. F., Sapata, V. D. M. R., Lopes, P. R. M., de Moraes, P. B., Montagnolli, R. N., Ferreira, H., & Bidoia, E. D. (2022). Antibacterial action and target mechanisms of zinc oxide nanoparticles against bacterial pathogens. Scientific Reports, 12, 2658. Merkl, P., Long, S., McInerney, G. M., & Sotiriou, G. A. (2021). Antiviral activity of silver, copper oxide and zinc oxide nanoparticle coatings against SARS-CoV-2. Nanomaterials, 11, 1312. Metwally, A. A., Abdel-Hady, A. N. A., Haridy, M. A., Ebnalwaled, K., Saied, A. A., & Soliman, A.  S. (2021). Wound healing properties of green (using Lawsonia inermis leaf extract) and chemically synthesized ZnO nanoparticles in albino rats. Environmental Science and Pollution Research, 29, 1–13. Miri, A., Khatami, M., Ebrahimy, O., & Sarani, M. (2020). Cytotoxic and antifungal studies of biosynthesized zinc oxide nanoparticles using extract of Prosopis farcta fruit. Green Chemistry Letters and Reviews, 13(1), 27–33. Mirzaei, H., & Darroudi, M. (2017). Zinc oxide nanoparticles: Biological synthesis and biomedical applications. Ceramics International, 43, 907–914. Mohamed, A. A., Fouda, A., Abdel-Rahman, M. A., Hassan, S. E. D., El-Gamal, M. S., Salem, S.  S., & Shaheen, T.  I. (2019). Fungal strain impacts the shape, bioactivity and multifunctional properties of green synthesized zinc oxide nanoparticles. Biocatalysis and Agricultural Biotechnology, 19, 101103. Murugan, M., Rani, K.  B., Wins, J.  A., Ramachandran, G., Guo, F., Mothana, R.  A., Noman, O. M., Nasr, F. A., & Siddiqi, M. Z. (2022). Green synthesized ZnO NPs as effective bacterial inhibitor against isolated MDRs and biofilm producing bacteria isolated from urinary tract infections. Journal of King Saud University-Science, 34, 101737. Nagarajan, S., & Arumugam Kuppusamy, K. (2013). Extracellular synthesis of zinc oxide nanoparticle using seaweeds of gulf of Mannar, India. Journal of Nanobiotechnology, 11, 1–11. Nageh, H., Emam, M. H., Ali, F., Abdel Fattah, N. F., Taha, M., Amin, R., Kamoun, E. A., Loutfy, S. A., & Kasry, A. (2022). Zinc oxide nanoparticle-loaded electrospun polyvinylidene fluoride nanofibers as a potential face protector against respiratory viral infections. ACS Omega, 7, 14887–14896. Nasrollahzadeh, M. S., Ghodsi, R., Hadizadeh, F., Maleki, M., Mashreghi, M., & Poy, D. (2022). Zinc oxide nanoparticles as a potential agent for antiviral drug delivery development: A systematic literature review. Current Nanoscience, 18, 147–153. Naveed Ul Haq, A., Nadhman, A., Ullah, I., Mustafa, G., Yasinzai, M., & Khan, I. (2017). Synthesis approaches of zinc oxide nanoparticles: The dilemma of ecotoxicity. Journal of Nanomaterials, 2017, 1–15. Ndlovu, S.  P., Fonkui, T.  Y., Kumar, P., Choonara, Y.  E., Ndinteh, D.  T., & Aderibigbe, B.  A. (2022). Dissolvable zinc oxide nanoparticle-loaded wound dressing with preferential exudate absorption and hemostatic features. Polymer Bulletin, 1–28. https://doi.org/10.1007/ s00289-­022-­04358-­0

146

B. A. Aderibigbe

Norouzi, M. A., Montazer, M., Harifi, T., & Karimi, P. (2021). Flower buds like PVA/ZnO composite nanofibers assembly: Antibacterial, in vivo wound healing, cytotoxicity and histological studies. Polymer Testing, 93, 106914. Orazizadeh, M., Khodadadi, A., Bayati, V., Saremy, S., Farasat, M., & Khorsandi, L. (2015). In vitro toxic effects of zinc oxide nanoparticles on rat adipose tissue-derived mesenchymal stem cells. Cell Journal (Yakhteh), 17, 412. Oteiza, P.  I. (2012). Zinc and the modulation of redox homeostasis. Free Radical Biology and Medicine, 53, 1748–1759. Padalia, H., & Chanda, S. (2017). Characterization, antifungal and cytotoxic evaluation of green synthesized zinc oxide nanoparticles using Ziziphus nummularia leaf extract. Artificial Cells, Nanomedicine, and Biotechnology, 45, 1751–1761. Paramadini, A. W., Chinavinijkul, P., Meemai, A., Thongkam, P., Apasuthirat, A., & Nasongkla, N. (2023). Fabrication and in vitro characterization of zinc oxide nanoparticles and hyaluronic acid-containing carboxymethylcellulose gel for wound healing application. Pharmaceutical Development and Technology, 1–17. https://doi.org/10.1080/10837450.2022.2164304 Patel, P., Kansara, K., Senapati, V. A., Shanker, R., Dhawan, A., & Kumar, A. (2016). Cell cycle dependent cellular uptake of zinc oxide nanoparticles in human epidermal cells. Mutagenesis, 31, 481–490. Patil, B.  N., & Taranath, T.  C. (2016). Limonia acidissima L. leaf mediated synthesis of zinc oxide nanoparticles: A potent tool against Mycobacterium tuberculosis. International Journal of Mycobacteriology, 5, 197–204. Pei, X., Jiang, H., Xu, G., Li, C., Li, D., & Tang, S. (2022). Lethality of zinc oxide nanoparticles surpasses conventional zinc oxide via oxidative stress, mitochondrial damage and calcium overload: A comparative hepatotoxicity study. International Journal of Molecular Sciences, 23, 6724. Pillai, A. M., Sivasankarapillai, V. S., Rahdar, A., Joseph, J., Sadeghfar, F., Rajesh, K., & Kyzas, G. Z. (2020). Green synthesis and characterization of zinc oxide nanoparticles with antibacterial and antifungal activity. Journal of Molecular Structure, 1211, 128107. Pineda-Reyes, A. M., & Olvera, M. D. L. L. (2018). Synthesis of ZnO nanoparticles from waterin-­oil (w/o) microemulsions. Materials Chemistry and Physics, 203, 141–147. Pokrowiecki, R., Szałaj, U., Fudala, D., Zaręba, T., Wojnarowicz, J., Łojkowski, W., Tyski, S., Dowgierd, K., & Mielczarek, A. (2022). Dental implant healing screws as temporary oral drug delivery systems for decrease of infections in the area of the head and neck. International Journal of Nanomedicine, 1679–1693. Qiu, D., Zhou, P., Kang, J., Chen, Z., Xu, Z., Yang, H., Tao, J., & Ai, F. (2022). ZnO nanoparticle modified chitosan/borosilicate bioglass composite scaffold for inhibiting bacterial infection and promoting bone regeneration. Biomedical Materials, 17, 065023. Rabecca, R., Doss, A., Kensa, V.  M., Iswarya, S., Mukeshbabu, N., Pole, R.  P., & Iyappan, K. (2022). Facile synthesis of zinc oxide nanoparticle using algal extract and their antibacterial potential. Biomass Conversion and Biorefinery, 1–12. Rabiee, N., Bagherzadeh, M., Ghadiri, A. M., Kiani, M., Aldhaher, A., Ramakrishna, S., Tahriri, M., Tayebi, L., & Webster, T.  J. (2020). Green synthesis of ZnO NPs via Salvia hispanica: Evaluation of potential antioxidant, antibacterial, mammalian cell viability, H1N1 influenza virus inhibition and photocatalytic activities. Journal of Biomedical Nanotechnology, 16, 456–466. Rajashekara, S., Shrivastava, A., Sumhitha, S., & Kumari, S. (2020). Biomedical applications of biogenic zinc oxide nanoparticles manufactured from leaf extracts of Calotropis gigantea (L.) Dryand. BioNanoScience, 10, 654–671. Rajeshkumar, S., Kumar, S. V., Ramaiah, A., Agarwal, H., Lakshmi, T., & Roopan, S. M. (2018). Biosynthesis of zinc oxide nanoparticles using Mangifera indica leaves and evaluation of their antioxidant and cytotoxic properties in lung cancer (A549) cells. Enzyme and Microbial Technology, 117, 91–95.

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

147

Raliya, R., Tarafdar, J. C., & Biswas, P. (2016). Enhancing the mobilization of native phosphorus in the mung bean rhizosphere using ZnO nanoparticles synthesized by soil fungi. Journal of Agricultural and Food Chemistry, 64(16), 3111–3118. Rao, K. M., Suneetha, M., Park, G. T., Babu, A. G., & Han, S. S. (2020). Hemostatic, biocompatible, and antibacterial non-animal fungal mushroom-based carboxymethyl chitosan-ZnO nanocomposite for wound-healing applications. International Journal of Biological Macromolecules, 155, 71–80. Rossi, A., Martins, M. P., Bitencourt, T. A., Peres, N. T., Rocha, C. H., Rocha, F. M., Neves-da-­ Rocha, J., Lopes, M. E., Sanches, P. R., Bortolossi, J. C., & Martinez-Rossi, N. M. (2021). Reassessing the use of undecanoic acid as a therapeutic strategy for treating fungal infections. Mycopathologia, 186, 327–340. Roy, R., Das, M., & Dwivedi, P. D. (2015). Toxicological mode of action of ZnO nanoparticles: Impact on immune cells. Molecular Immunology, 63, 184–192. Saddik, M.  S., Elsayed, M., El-Mokhtar, M.  A., Sedky, H., Abdel-Aleem, J.  A., Abu-Dief, A.  M., Al-Hakkani, M.  F., Hussein, H.  L., Al-Shelkamy, S.  A., Meligy, F.  Y., & Khames, A. (2022). Tailoring of novel azithromycin-loaded zinc oxide nanoparticles for wound healing. Pharmaceutics, 14(1), 1–23. Şahin, B., Aydin, R., Soylu, S., Türkmen, M., Kara, M., Akkaya, A., Çetin, H., & Ayyıldız, E. (2022). The effect of thymus syriacus plant extract on the main physical and antibacterial activities of ZnO nanoparticles synthesized by SILAR method. Inorganic Chemistry Communications, 135, 109088. Sánchez-López, E., Gomes, D., Esteruelas, G., Bonilla, L., Lopez-Machado, A. L., Galindo, R., Cano, A., Espina, M., Ettcheto, M., Camins, A., & Silva, A. M. (2020). Metal-based nanoparticles as antimicrobial agents: An overview. Nanomaterials, 10, 292. Santhoshkumar, J., Kumar, S.  V., & Rajeshkumar, S. (2017). Synthesis of zinc oxide nanoparticles using plant leaf extract against urinary tract infection pathogen. Resource-Efficient Technologies, 3, 459–465. Sarkar, D., Tikku, S., Thapar, V., Srinivasa, R. S., & Khilar, K. C. (2011). Formation of zinc oxide nanoparticles of different shapes in water-in-oil microemulsion. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 381, 123–129. Sarkar, J., Ghosh, M., Mukherjee, A., Chattopadhyay, D., & Acharya, K. (2014). Biosynthesis and safety evaluation of ZnO nanoparticles. Bioprocess and Biosystems Engineering, 37, 165–171. Shafiee, P., Nafchi, M.  R., Eskandarinezhad, S., Mahmoudi, S., & Ahmadi, E. (2021). Sol-gel zinc oxide nanoparticles: Advances in synthesis and applications. Synthesis and Sintering, 1, 242–254. Sharma, R. K., & Ghose, R. (2015). Synthesis of zinc oxide nanoparticles by homogeneous precipitation method and its application in antifungal activity against Candida albicans. Ceramics International, 41, 967–975. Sharma, R., Sharma, R., Singh, R. R., & Kumari, A. (2023). Evaluation of biogenic zinc oxide nanoparticles from Tinospora cordifolia stem extract for photocatalytic, anti-microbial, and antifungal activities. Materials Chemistry and Physics, 297, 127382. Shayani Rad, M., Sabeti, Z., Mohajeri, S. A., & Fazly Bazzaz, B. S. (2020). Preparation, characterization, and evaluation of zinc oxide nanoparticles suspension as an antimicrobial media for daily use soft contact lenses. Current Eye Research, 45, 931–939. Sirelkhatim, A., Mahmud, S., Seeni, A., Kaus, N. H. M., Ann, L. C., Bakhori, S. K. M., Hasan, H., & Mohamad, D. (2015). Review on zinc oxide nanoparticles: Antibacterial activity and toxicity mechanism. Nano-Micro Letters, 7, 219–242. Soliman, G. M. (2017). Nanoparticles as safe and effective delivery systems of antifungal agents: Achievements and challenges. International Journal of Pharmaceutics, 523, 15–32. Song, Y., Yin, F., Zhang, C., Guo, W., Han, L., & Yuan, Y. (2021). Three-dimensional ordered mesoporous carbon spheres modified with ultrafine zinc oxide nanoparticles for enhanced microwave absorption properties. Nano-Micro Letters, 13, 1–16.

148

B. A. Aderibigbe

Souza, J. M. T., de Araujo, A. R., de Carvalho, A. M. A., Amorim, A. D. G. N., Daboit, T. C., de Almeida, J. R. D. S., da Silva, D. A., & Eaton, P. (2020). Sustainably produced cashew gum-­ capped zinc oxide nanoparticles show antifungal activity against Candida parapsilosis. Journal of Cleaner Production, 247, 119085. Sun, Y., Zhang, W., Wang, M., Liu, H., Li, Q., Luo, J., Zhao, M., Liu, S., & Wang, X. (2023). Terbium-doped zinc oxide constructed dual-light-responsive nitric oxide-releasing platform for bacterial keratitis treatment. Nano Research, 16, 849–857. Tapiero, H., & Tew, K. D. (2003). Trace elements in human physiology and pathology: Zinc and metallothioneins. Biomedicine and Pharmacotherapy, 57, 399–411. Tavakoli, A., Ataei-Pirkooh, A., Mm Sadeghi, G., Bokharaei-Salim, F., Sahrapour, P., Kiani, S. J., Moghoofei, M., Farahmand, M., Javanmard, D., & Monavari, S.  H. (2018). Polyethylene glycol-­coated zinc oxide nanoparticle: An efficient nanoweapon to fight against herpes simplex virus type 1. Nanomedicine, 13, 2675–2690. Terea, H., Selloum, D., Rebiai, A., Bouafia, A., & Ben Mya, O. (2023). Preparation and characterization of cellulose/ZnO nanoparticles extracted from peanut shells: Effects on antibacterial and antifungal activities. Biomass Conversion and Biorefinery, 1–12. https://doi.org/10.1007/ s13399-­023-­03959-­7 Tiwari, V., Mishra, N., Gadani, K., Solanki, P. S., Shah, N. A., & Tiwari, M. (2018). Mechanism of anti-bacterial activity of zinc oxide nanoparticle against carbapenem-resistant Acinetobacter baumannii. Frontiers in Microbiology, 9, 1218. Torabi, L. R. (2017). The antibacterial effects of Zno nanoparticles on patients with urinary tract infection isolated from Alzahra Hospital in Isfahan, Iran. Zahedan Journal of Research in Medical Sciences, 19, 1–6. Unemo, M., & Nicholas, R.  A. (2012). Emergence of multidrug-resistant, extensively drug-­ resistant and untreatable gonorrhea. Future Microbiology, 7, 1401–1422. Vasudevan, S., Srinivasan, P., Rayappan, J. B. B., & Solomon, A. P. (2020). A photoluminescence biosensor for the detection of N-acyl homoserine lactone using cysteamine functionalized ZnO nanoparticles for the early diagnosis of urinary tract infections. Journal of Materials Chemistry B, 8(19), 4228–4236. Vijayakumar, S., Nilavukkarasi, M., & Sakthivel, B. (2020). Bio-synthesized zinc oxide nanoparticles for anti-tuberculosis agent: Scientifically unexplored. Gene Reports, 20, 100764. Wang, Y., Zhang, X., Wang, A., Li, X., Wang, G., & Zhao, L. (2014). Synthesis of ZnO nanoparticles from microemulsions in a flow type microreactor. Chemical Engineering Journal, 235, 191–197. Wang, Z., Mei, L., Liu, X., & Zhou, Q. (2021a). Hierarchically hybrid biocoatings on Ti implants for enhanced antibacterial activity and osteogenesis. Colloids and Surfaces B: Biointerfaces, 204, 111802. Wang, Z., Wang, X., Wang, Y., Zhu, Y., Liu, X., & Zhou, Q. (2021b). NanoZnO-modified titanium implants for enhanced anti-bacterial activity, osteogenesis and corrosion resistance. Journal of Nanobiotechnology, 19, 1–23. Wang, W., Liu, M., Shafiq, M., Li, H., Hashim, R., Mohamed, E. N., Hany, E. H., Morsi, Y., & Mo, X. (2023). Synthesis of oxidized sodium alginate and its electrospun bio-hybrids with zinc oxide nanoparticles to promote wound healing. International Journal of Biological Macromolecules, 232, 123480. Wen, Z., Shi, X., Li, X., Liu, W., Liu, Y., Zhang, R., Yu, Y., & Su, J. (2023). Mesoporous TiO2 coatings regulate ZnO nanoparticle loading and Zn2+ release on titanium dental implants for sustained osteogenic and antibacterial activity. ACS Applied Materials and Interfaces, 15, 15235–15249. Wilkinson, H. N., & Hardman, M. J. (2020). Wound healing: Cellular mechanisms and pathological outcomes. Open Biology, 10, 200223. Yan, G., Huang, Y., Bu, Q., Lv, L., Deng, P., Zhou, J., Wang, Y., Yang, Y., Liu, Q., Cen, X., & Zhao, Y. (2012). Zinc oxide nanoparticles cause nephrotoxicity and kidney metabolism alterations in rats. Journal of Environmental Science and Health, Part A, 47, 577–588.

Zinc Oxide Nanoparticles in Biomedical Applications: Advances in Synthesis…

149

Yang, X., Liu, X., Lu, H., Zhang, X., Ma, L., Gao, R., & Zhang, Y. (2012). Real-time investigation of acute toxicity of ZnO nanoparticles on human lung epithelia with hopping probe ion conductance microscopy. Chemical Research in Toxicology, 25, 297–304. Yang, Y., Tao, B., Gong, Y., Chen, R., Yang, W., Lin, C., Chen, M., Qin, L., Jia, Y., & Cai, K. (2020). Functionalization of Ti substrate with pH-responsive naringin-ZnO nanoparticles for  the reconstruction of large bony after osteosarcoma resection. Journal of Biomedical Materials Research Part A, 108, 2190–2205. Yao, S., Feng, X., Lu, J., Zheng, Y., Wang, X., Volinsky, A. A., & Wang, L. N. (2018). Antibacterial activity and inflammation inhibition of ZnO nanoparticles embedded TiO2 nanotubes. Nanotechnology, 29, 244003. Yassin, M. T., Mostafa, A. A. F., Al-Askar, A. A., & Al-Otibi, F. O. (2022). Facile green synthesis of zinc oxide nanoparticles with potential synergistic activity with common antifungal agents against multidrug-resistant candidal strains. Crystals, 12, 774. Yıldırım, Ö. A., & Durucan, C. (2010). Synthesis of zinc oxide nanoparticles elaborated by microemulsion method. Journal of Alloys and Compounds, 506, 944–949. Yousef, M. I., Mutar, T. F., & Kamel, M. A. E. N. (2019). Hepato-renal toxicity of oral sub-chronic exposure to aluminum oxide and/or zinc oxide nanoparticles in rats. Toxicology Reports, 6, 336–346. Yuvaraj, A., Priyadharshini, R., Kumar, R., & Sinduja, P. (2023). Anti-inflammatory and antifungal activity of zinc oxide nanoparticle using red sandalwood extract. Journal of Population Therapeutics and Clinical Pharmacology, 30, 172–182. Zhang, R., Liu, X., Xiong, Z., Huang, Q., Yang, X., Yan, H., Ma, J., Feng, Q., & Shen, Z. (2018). Novel micro/nanostructured TiO2/ZnO coating with antibacterial capacity and cytocompatibility. Ceramics International, 44, 9711–9719.

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral Applications Pranav Pandya and Sougata Ghosh

Introduction Compared to their bulkier counterpart, the nanoparticles (NPs) in size ranging from 1 to 100 nm have unique physical and chemical properties. They have a larger surface area-to-volume ratio (Roopan & Khan, 2021). Their thermal, optical, photochemical, electrical, energy, catalytic, and therapeutic properties are also exceptional that make them suitable for diverse applications (Hemalatha et al., 2013; Sagadevan et al., 2022; Jadoun et al., 2021). Nanoparticles of unique dimensions can be further translated into various products by industries associated with food, agriculture, and pharmaceuticals (Drummer et al., 2021). The transition metals with partially filled d-orbitals in their atomic electronic configuration give them the ability to acquire different oxidation states that rationalize their wide range of applications in cosmetics, environment, medicine, fuel cells, sensors, energy storage, catalysis, and semiconductors (Santos et al., 2015; Dizaj et al., 2014; Guo et al., 2019). Among different metal nanoparticles with elemental gold (Au), zinc (Zn), titanium (Ti), silver (Ag), and copper (Cu), the titanium dioxide nanoparticles (TiO2NPs) are considered the most promising that amounts to their large-scale production every year globally (Piccinno et al., 2012). Their less expensive, chemically stable nature, higher refractive index, higher chances of oxidation, and their lattice structure with oxygen vacancies make them ideal for numerous applications (Aslam et al., 2021). The TiO2NPs are white-colored powders, which have a higher refractive index (n) of around 2.4 and are insoluble in water (Nabi et  al., 2018). They basically exist in three different polymorphic forms with the crystalline structure namely anatase, rutile, and brookite. The TiO2NPs are also used in sensors, wastewater treatment, photocatalysis, antimicrobial agents, food additives, and cosmetics P. Pandya · S. Ghosh (*) Department of Microbiology, School of Science, RK. University, Rajkot, Gujarat, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_7

151

152

P. Pandya and S. Ghosh

(Lazar et al., 2012; Zhang et al., 2012; Dastjerdi & Montazer, 2010; Kubacka et al., 2014; Blecher et al., 2011; Nohynek et al., 2007). Two different conventional approaches were mainly employed for the synthesis of metal oxide NPs: the top-down and the bottom-up approach (Iravani, 2011; Mittal et  al., 2013; Wang et  al., 2020). Compared to the top-down approach, the bottom-up approach has attracted greater attention as it provides an advantage in controlling the size and shape of the resulting NPs. The biological methods are advantageous over chemical methods associated with certain drawbacks such as expensive nature, greater energy consumption, involvement of toxic and volatile reagents, and hazards to environment as well as human life (Nadeem et al., 2018; Subhapriya & Gomathipriya, 2018). The green synthesis approach for the fabrication of metal oxide NPs may involve bacteria, fungi, algae, and plants along with their metabolites (Ghosh & Webster, 2021a; Bloch et al., 2021; Gami et al., 2022; Buazar et al., 2016). The present chapter explains the various green synthesis approaches for the synthesis of TiO2NPs with different biomedical applications such as antimicrobial and antiviral that are listed in Table 1.

Bacteriogenesis Bacterial enzymes and proteins are responsible for reducing the metal ions to respective nanoparticles followed by their stabilization (Ghosh, 2018). Several bacteria are explored for their role in the synthesis of TiO2NPs that are discussed in this section. Jayaseelan et al. (2013) developed a biological approach for TiO2NP fabrication from Aeromonas hydrophila and further investigated their antibacterial activity. Firstly, the bacterial culture was grown in an altered nutrient broth containing 1% beef extract, 0.5% NaCl, 1% peptone, and pH 7. The culture medium was incubated for 24 h under shaking conditions (120 rpm) at 30 °C, which was followed by diluting 25 mL of culture with sterile nutrients containing distilled water (75 mL). The solution was further placed for another 24  h in order to permit the bacterial growth, which was followed by incubation at 30 °C for 24 h with shaking at 120 rpm. After mixing 20 mL TiO(OH)2 (5 mM) with the aforementioned reaction mixture, the development of white precipitate was noticed that confirmed the successful formation of TiO2NPs. The mixture was air-dried after 24 h to obtain the powder. The Fourier transform infrared spectroscopy (FTIR) analysis identified the absorbance peaks at 3430, 1643, 2937, 1079, and 1403 cm−1, which attributed to the alcohols, primary amines, phenols, aliphatic amines, and lactones present in the metabolites of A. hydrophila taking part in the TiO2NPs synthesis. The rutile phase of fabricated NPs was determined from X-ray diffraction (XRD) analysis along with their crystalline size (40.50  nm). The atomic force microscope (AFM) studies showed the rough surface of TiO2NPs, which converted to smooth layers at the highest TiO2NP concentration. The uniform distribution of the particles on the surface along with the formation of agglomerates was observed. The size of the particles was in a range

Spherical Irregular

40–60 30–80 8

43–67 –

62–74

80–120 – 10–400

Bacteria

Bacteria Bacteria

Bacteria

Fungi

Fungi

Fungi Fungi Fungi

Bacillus mycoides

Bacillus sp. Rummeliibacillus pycnus M1, Acinetobacter baumannii S1, Acinetobacter seohaensis N3, and Bacillus cereus A1 Streptomyces sp. HC1

Alternaria solani

Aspergillus flavus

Fomes fomentarius Fomitopsis pinicola Trichoderma citrinoviride

Irregular Irregular Irregular, triangular, pentagonal, spherical, and rod-shape

Spherical

Spherical Spherical

Spherical

Size (nm) Shape 28–54 –

Type Bacteria

Source Aeromonas hydrophila

Table 1  Antimicrobial activity of biogenic TiO2NPs

Staphylococcus aureus, Escherichia coli, and Candida albicans Klebsiella aerogenes, Escherichia coli, Staphylococcus aureus, Pseudomonas desmolyticum, and Candida albicans Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Bacillus subtilis Escherichia coli and Staphylococcus aureus Escherichia coli and Staphylococcus aureus Pseudomonas aeruginosa

Candida albicans Klebsiella pneumoniae Streptococcus pneumoniae

Pathogens inhibited Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Streptococcus pyogenes, and Enterococcus faecalis Escherichia coli

(continued)

Rehman et al. (2020a) Rehman et al. (2020b) Arya et al. (2021)

Rajakumar et al. (2012)

Lingaraju et al. (2021)

Agceli et al. (2020)

Ordenes-Aenishanslins et al. (2014) Moradpoor et al. (2021) Meenatchisundaram et al. (2022)

References Jayaseelan et al. (2013)

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral… 153

Salmonella typhi, Escherichia coli, Klebsiella pneumoniae Clostridium tetani, Vibrio cholerae, Bacillus cereus, and Escherichia coli Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae, Enterococcus faecalis, and Bacillus subtilis Proteus vulgaris and Aspergillus niger Staphylococcus aureus

47 10–49

20–70 24

25

20–50 8 20–50 20–90

Plant

Plant

Plant Plant

Plant

Plant

Plant Plant Plant

Ledebouria revoluta

Luffa acutangula

Mentha arvensis Mulberry

Ocimum americanum

Orange peel

Piper betel Prunus yedoensis Trigonella foenum-graecum

Spherical Spherical and conjoint spherical Spherical Bacillus cereus, Salmonella paratyphi, Clostridium perfringens, Klebsiella pneumoniae, Candida albicans, and Aspergillus niger Angular Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli Spherical Staphylococcus aureus and Escherichia coli Spherical Staphylococcus aureus and Escherichia coli Spherical Yersinia enterocolitica, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, and Streptococcus faecalis

Hexagonal

Spherical

Spherical

15–45

Azadirachta indica

Pathogens inhibited – –

Size (nm) Shape 50 Spherical 90–150 Spherical

Type Algae Blue-green algae Plant

Source Chlorella pyrenoidosa Spirulina platensis

Table 1 (continued)

Amanulla and Sundaram (2019) Hunagund et al. (2016) Manikandan et al. (2018) Subhapriya and Gomathipriya (2018)

Vijayakumar et al. (2020)

Ahmad et al. (2020) Shimi et al. (2022)

Anbumani et al. (2022)

Aswini et al. (2021)

Thakur et al. (2019)

References Sharma et al. (2018) Vasanth et al. (2022)

154 P. Pandya and S. Ghosh

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

155

Fig. 1 (a, b) FE-SEM images of the A. hydrophila synthesized TiO2NPs. (Reprinted with permission from Jayaseelan et al. (2013) Copyright © 2013 Elsevier B.V.)

from 28 to 54 nm, while 40.50 nm size of single particle was revealed in the scanning electron microscope (SEM) images as evident from Fig. 1. The authors speculated the probable mechanism involved in the synthesis that indicates the picking up of hydrogen ion from glycyl-L-proline by one of the lone pairs of e¯ on the oxygen in the initial stage. The protonated TiO(OH)2 gives Ti3+ by losing a water molecule. Eventually, a hydrogen ion is pulled off from the Ti3+ resulting in the formation of the TiO2NPs. The antibacterial activity of TiO2NPs showed the highest zone of inhibition (ZOI) against Staphylococcus aureus (33 mm) followed by Escherichia coli (26  mm), Pseudomonas aeruginosa (25  mm), Streptococcus pyogenes (31  mm), and Enterococcus faecalis (29 mm), while the lowest was noted against A. hydrophila (23  mm). Minimum inhibitory concentration (MIC) of TiO2NPs evaluated against A. hydrophila, E. coli, P. aeruginosa, S. pyogenes, S. aureus, and E. faecalis were 25, 20, 30, 10, 10, and 15 μg/mL, respectively, as seen in Fig. 2. Ordenes-Aenishanslins et al. (2014) reported the fabrication of TiO2NPs using a Gram-positive bacteria Bacillus mycoides. Initially, 200 μL of the bacterial culture was added to 200 mL Luria-Bertani (LB) broth followed by incubation (150 rpm) for around 12 h under shaking condition. Then, 25 mM of TiO(OH)2 solution was further mixed and the reaction mixture was incubated under constant shaking conditions for 24 h at 37 °C. Furthermore, the incubation of the reaction mixture was carried out for a period of 8 h at room temperature, which resulted in the appearance of white precipitate, indicating the formation of TiO2NPs. The centrifugation (3820 g) of the reaction mixture was carried out for a period of 15 min in order to separate the precipitate. The precipitates obtained were further washed and centrifuged successively. The UV-vis analysis identified the absorption peak near 380 nm for the synthesized TiO2NPs, while the specific FTIR signals were observed at 450–700 cm−1, which was mainly due to the Ti-O-Ti bond of TiO2NPs. The surface functional groups occurring on NPs identified using FTIR analysis showed bands at different positions such as a wide band at 3431 cm−1 (stretching of O-H in alcoholic groups) and at 2985  cm−1 (C-H stretching). Additionally, C=O and N-H

156

P. Pandya and S. Ghosh

Fig. 2  Well-diffusion assay for TiO2NPs against A. hydrophila (a), E. coli (b), P. aeruginosa (c), S. aureus (d), S. pyogenes (e), and E. faecalis (f). (Reprinted with permission from Jayaseelan et al. (2013) Copyright © 2013 Elsevier B.V.)

vibration-­associated peaks at 1646, 1554, 1462, and 1400 cm−1 were also identified. The band at 1047 cm−1 was specific to C-N stretching, while the stretching of C=C ring was attributed to the bands at 1554 and 1400 cm−1. The biomolecules such as carbohydrates or peptides on NP’s surface played valuable role in capping and stabilization. The size of biosynthesized NPs ranged between 40 and 60 nm having a spherical morphology when identified via transmission electron microscope (TEM) analysis. The presence of an organic envelope around the NPs was also identified by TEM that might have participated in the substrate transformation and aided in the stabilization of NPs. A low toxic nature was suggested from the experiment performed toward the evaluation of the antibacterial activity of TiO2NPs. In another study, Moradpoor et  al. (2021) developed a biogenic process for TiO2NP synthesis from Bacillus sp. and studied its effect toward oral pathogen Candida albicans. The bacterial cell mass was developed by adding culture in the medium containing different glucose concentrations (0.50, 0.75, and 1 M) followed by incubation at 30 °C under shaking (160 rpm) for around 1 week. The centrifugation at 5000 rpm for 15 min of the derived biomass was carried out in order to collect the supernatant that was mixed with identical amounts of metatitanic acid (0.01, 0.05, and 0.1 M). The resulting mixture was incubated at 30 °C under shaking condition (120 rpm). The UV-vis analysis revealed an intense adsorption peak at 274 nm that was specific for TiO2NPs. The FTIR spectrum identified the peaks attributed to the stretching vibrations of the O-H group (2700–3500 cm−1), Ti-O tensile states

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

157

(400–800  cm−1), and Ti-O bond (657  cm−1). XRD analysis identified the anatase phase and the tetragonal crystalline structure (21  nm). SEM images showed the non-uniform distribution of the particles with particle size ranging around 30–80 nm average being 49 nm. TEM images indicated the spherical morphology of the particle (50 nm). The highest antifungal activity against C. albicans was equivalent to 71.66% inhibition for the TiO2NPs synthesized using 0.05 M metatitanic acid and 1 M glucose with an incubation time of 48 h. Meenatchisundaram et al. (2022) fabricated biogenic TiO2NPs via different bacterial species and investigated their antibacterial activity. The TiO2NPs were prepared by inoculating Rummeliibacillus pycnus M1, Acinetobacter baumannii S1, Acinetobacter seohaensis N3, and Bacillus cereus A1 in separate media containing the suitable nutrient sources. The cultures were grown for 24 h, and 0.1 M TiOCl2 (20 mL) was further supplemented to fresh culture (20 mL) followed by the maintenance of the solution at 50 °C for 20 min. Furthermore, the culture solution was cooled down and was further incubated for a period of 24 h at room temperature. Furthermore, the separation of the resulting precipitate was achieved using centrifugation at 5000 rpm for 10 min followed by 12 h of drying at 80 °C. The calcination performed at 450 °C for 90 min formed the dry powder. The samples lacking calcination were labeled as a1, a2, a3, and a4, while those with calcination were named b1, b2, b3, and b4, respectively. The samples obtained from R. pycnus M1, A. baumannii S1, A. seohaensis N3, and B. cereus A1 were labeled as M1, S1, N3, and A1, respectively. The UV-vis diffuse reflectance spectral (DRS) analysis identified the absorption peak at 340 nm and 323 nm for non-calcinated TiO2NPs and calcinated TiO2NPs (450 °C). The FTIR spectrum identified the characteristic peak of Ti-O and Ti-O-Ti bond vibrations (400–800 cm−1) and also the peaks attributing to the amines and phenolic groups at 1052 cm−1 from the bacterium, which played a role as a stabilizing and capping agent in TiO2NP fabrication. The morphological analysis of the particles via SEM revealed the agglomerated irregularly shaped particles and a few particles with spherical shapes. Energy-dispersive spectroscopy (EDS) revealed the occurrence of elemental Ti and O in the fabricated particles. The mean particle size evaluated using TEM was 8 nm. TiO2NPs showed anatase phase along with average crystalline sizes of 10, 7.8, 7.2, 9.2, 7.8, 9.2, 8.2, and 13.1 nm were noted for a1, a2, a3, a4, b1, b2, b3, and b4, respectively, in XRD analysis. The antibacterial activity of the synthesized TiO2NPs was tested against Klebsiella pneumoniae and Streptococcus pneumoniae. All TiO2NP samples showed the highest ZOI against K. pneumoniae and S. pneumoniae at 50 μL concentration. Agceli et al. (2020) employed a rapid approach for TiO2NP formation by utilizing Streptomyces sp. HC1. Initially, a single loop of colony was added under shaking condition and incubated at 37  °C for 24  h. Next, about 20  mL of 0.025  M TiO(OH)2 solution was mixed in culture flask followed by 30 min of incubation at 60 °C. Centrifugation resulted in the separation of the formed precipitate that was further maintained at neutral pH by washing in distilled water. The highest yield of NPs was obtained at 30:15 TiO(OH)2 concentration at pH 6.5. SEM images indicated the spherical morphology of the particles that were around 43–67 nm in size. The intense diffraction 2θ peaks at 25°, 37°, 48°, and 55° were identified from the

158

P. Pandya and S. Ghosh

XRD spectrum, which reflected the crystal planes 101, 004, 200, and 211, respectively. The size of the particles from 32 to 40 nm with the presence of homogenous grooves was indicated from the AFM analysis. FTIR studies showed the Ti-O-Ti peaks at 1138–1050  cm−1 suggesting successful formation of the TiO2NPs that exhibited a maximum ZOI against S. aureus (12 mm) and E. coli (12 mm) followed by C. albicans (8 mm) providing strong evidence about the antimicrobial property of the bacteriogenic TiO2NPs.

Mycogenesis Various fungi can synthesize TiO2NPs, referred to as mycogenesis, with attractive properties. Lingaraju et al. (2021) fabricated biocompatible TiO2NPs utilizing the fungal biomass of Alternaria solani. Initially, the fungal strain was inoculated in the sterilized potato dextrose broth (PDB) at pH 5.1 ± 0.2 in an aseptic condition followed by incubating it under shaking condition at 100 rpm for 7 days at 25 °C. The fungal mycelium was separated via centrifugation followed by washing for four to five times with double-distilled water and drying it subsequently. TiO2NP fabrication using biomass of A. solani was initiated by dissolving 10 mL fungal suspension (1 mg/1 mL) in 90 mL titanium (IV) butoxide (1 mM) followed by homogenizing the mixture under shaking conditions (100  rpm) for 7  days at room temperature (RT). The successful fabrication of NPs was suggested by the appearance of the white precipitate that was collected after centrifugation at 5000 rpm for 20 min. The pellet was then washed using double-distilled water and ethanol followed by drying overnight at 100 °C eventually crushing it into fine powder. The DRS studies of the TiO2NPs identified the absorption spectra between 200 and 700 nm along with a reflectance peak at 330 nm. The FTIR spectra of the particles exhibited the peaks specific to the stretching vibrations of C=C (1627 cm−1), O-H (3400 cm−1), Ti-O (648 cm−1), and C-H (1400 cm−1). The powder X-ray diffraction (PXRD) analysis detected the crystalline anatase structure of the particles. The morphological analysis of the TiO2NPs employing SEM demonstrated agglomerated irregular structures, while the energy-dispersive X-ray (EDX) analysis confirmed the existence of elemental Ti and O. The antimicrobial testing of the synthesized TiO2NPs was verified against S. aureus, E. coli, Pseudomonas desmolyticum, Klebsiella aerogenes, and C. albicans using agar well-diffusion method. The highest ZOI for TiO2NPs (400 μg/ mL) was observed against K. aerogenes (7.53  ±  0.13  mm) followed by E. coli (6.17 ± 0.03 mm), S. aureus (5.87 ± 0.03 mm), and P. desmolyticum (5.07 ± 0.09 mm). The fungicidal activity against C. albicans was confirmed from ZOI equivalent to 6.97 ± 0.09 mm at 400 μg/mL TiO2NPs. The probable mechanism behind the antimicrobial activity of the TiO2NPs was an alteration of the plasma membrane permeability and impairment of the membrane transport. Furthermore, the denaturation of DNA and protein might have caused cellular damage. Rajakumar et al. (2012) fabricated TiO2NPs from the fungus Aspergillus flavus and further investigated its activity against pathogenic bacteria. The biomass of

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

159

fungi was developed under aerobic condition by the growth of A. flavus using the liquid medium composed of K2HPO4 (2 g/L), KH2PO4 (7 g/L), (NH4)2SO4 (1 g/L), MgSO4.7H2O (0.1 g/L), glucose (10 g/L), and yeast extract (0.6 g/L). The pH of the solution was adjusted to 6.2 ± 0.2 followed by inoculation and incubation at 200 rpm for 5  days at 37  °C.  The mycelium obtained after incubation was separated and washed. The freshly washed mycelium (5 g) was mixed with 100 mL TiO2 (1 mM) solution followed by incubation in dark conditions under shaking at 200 rpm and 37 °C. The FTIR analysis revealed the characteristic peaks of Ti-O-O bond vibrations at 590 cm−1 and suggested the occurrence of Ti-O bonds and the lack of peroxo and -OH groups in the final product. The different absorption peaks attributing to asymmetrical C=O coupled vibration of the anhydride group (1779 cm−1), change in carbonyl region (1600–1800  cm−1), and amide I and amide II (1779 and 1639 cm−1) were also noted. The formation of new bands at 1779 and 1639 cm−1 of amide I and II suggested the occurrence of amino acid residues (from the fungal matrix). The XRD identified the pure anatase phase of the TiO2 with a crystalline size between 62 and 74 nm. AFM images identified particles having porous rough surface along with the aggregated structure with the height of the particles around 10 nm. SEM images indicated the spherical aggregated structure. The TiO2NPs with polydispersed nature possessing spherical and hexagonal shapes with size 60 ± 5 nm were revealed in the TEM images. The synthesized TiO2NPs demonstrated antibacterial activity against S. aureus, E. coli, P. aeruginosa, K. pneumoniae, and Bacillus subtilis with the ZOI of 25, 35, 27, 18, and 22  mm, respectively. The MIC of TiO2NPs was around 40 μg/mL (E. coli), 40 μg/mL (S. aureus), 70 μg/mL (K. pneumoniae), 80 μg/mL (P. aeruginosa), and 45 μg/mL (B. subtilis). Rehman et al. (2020a) identified an alternative way to synthesize TiO2NPs from the wild mushroom Fomes fomentarius. The NPs were synthesized by using dry fungal powder and 1 mM titanium (IV) isopropoxide. The UV-vis spectra showed peaks at 410 nm for the rutile phase and at 700 nm for the agglomerated NPs. The XRD analysis revealed particles having a crystalline nature. The absorption peaks between 766 and 1630 cm−1 noted in FTIR analysis were due to the presence of the TiO2NPs. SEM images revealed the rough and irregular surface of the TiO2NPs with the formation of aggregated structures, while the TEM analysis identified particle asymmetry and the 80–120 nm mean particle size as seen in Fig. 3. The ZOI of 15 and 11 mm against E. coli and S. aureus confirmed the potent antibacterial activity of the mycogenic TiO2NPs. Rehman et al. (2020b) utilized wild mushroom Fomitopsis pinicola for the fabrication of TiO2NPs and further studied its antibacterial activity. Initially, 10 g dried fungal powder and 100 mL Millipore water were mixed and sonicated for 25–30 min. Furthermore, the centrifugation (4000 rpm) of the reaction mixture resulted in the formation of clarified solution. The resulting solution was filtered out of which around 10 mL filtrate was added in 100 mL titanium (IV) isopropoxide (1 mM) (Ti (OC3H7)4) followed by agitation at room temperature till the color changed. The obtained NPs were filtered, ethanol washed, and centrifuged at 4000 rpm for 10 min at 10 °C. The XRD images revealed the rutile phase of TiO2NPs. FTIR spectrum identified hydroxyl functional groups (1664 and 3480 cm−1) and further confirmed

160

P. Pandya and S. Ghosh

Fig. 3  Morphological study of TiO2NPs—(a) scanning electron microscopy (SEM) and (b) transmission electron microscope (TEM) images of TiO2 NPs. (Reprinted from Rehman et al. (2020a))

the occurrence of TiO2 from the peaks at 460, 597, and 777 cm−1 specific to Ti-O. The elongated peaks ranging 1000–1800 cm−1 suggested numerous functional groups in the mushroom extract and linear aliphatic amines (C-N) that were evident from the peak at 1000–1040 cm−1. Thus, it was speculated from the FTIR analysis that the active components such as methyl, amino, and hydroxyl groups in the mushroom extract played the role of an effective bio-reductant in the TiO2NP formation. SEM images suggested the dispersed nature of the rough-surfaced NPs in an irregular manner, while the TEM images revealed their irregular shape. The TiO2NPs showed the MIC value of 62.5 μg/mL against both E. coli and S. aureus and the minimum bacterial concentration (MBC) values (MIC/MBC) of 62.5/125 μg/mL (E. coli) and 62.5/125 μg/mL (S. aureus). Arya et al. (2021) reported biogenic TiO2NPs from Trichoderma citrinoviride extract and further analyzed their antibacterial activity toward drug-resistant P. aeruginosa clinical isolates (PA01 and PA02). Initially, T. citrinoviride was inoculated in PDB and incubated for 7  days at 25  °C under shaking condition (150  rpm). The obtained mycelial suspension was further filtered and collected separately, which was washed with sterile distilled water. The 5 g dried mycelial biomass was suspended in 100  mL sterile distilled water followed by overnight incubation. The cell lysate obtained after 15 min of centrifugation of the mycelial solution at 10,000  rpm (4  °C) was used in TiO2NP fabrication. The mixture of 0.2  mL nitric acid (HNO3), 10  mL titanium isopropoxide, 90  mL ethanol, and 10 mL mycelial cell lysate were stirred, incubated for 30 min, dried, and calcinated at 450 °C for 2 h in a furnace to obtain the powdered form of TiO2NPs. The successful synthesis of TiO2NPs was suggested from the strong absorbance at 400 nm obtained during UV-visible spectroscopy analysis of the particles. The FTIR spectral studies of the TiO2NPs revealed a strong absorbance below 1200 cm−1 (Ti-O-Ti stretching), 1400–1600  cm−1 stretching vibrations (C=C) and 3000–3100  cm−1

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

161

(C-H), and peaks at 1670–1820 cm−1 (C=O). The field emission scanning electron microscope (FE-SEM) analysis of the TiO2NPs revealed triangular, spherical, irregular, pentagonal, and rod-shaped particles with 10–400 nm size. TiO2NPs possessed 10–396 nm of hydrodynamic size distribution (Z-average) and 29.5 mV of zeta potential value. The zeta potential value closer to +30 mV suggested the prominent cationic nature and higher stability of TiO2NPs. The high particle homogeneity was indicated by the low (0.327) polydispersity index (PDI). The purity of fabricated TiO2NPs was confirmed from XRD analysis, which revealed the peaks only for anatase and rutile phases. The crystalline size of the anatase phase (53 nm) and rutile phase (66 nm) was calculated from Debye-Scherrer’s formula. The complete inhibition of PA01 and PA02 was obtained on treatment with TiO2NPs at a concentration of 100 μg/mL, which confirmed the antibacterial activity of TiO2NPs against drug-resistant P. aeruginosa.

Phycogenesis Algae-mediated synthesis of various nanoparticles is known as the phycogenic approach. Sharma et al. (2018) developed a novel method for TiO2NP synthesis using the microalgae Chlorella pyrenoidosa. The fine powder was prepared by drying and pulverizing the algal biomass. The fine powder (0.4 g) was added to 40 mL deionized water, and the extract was prepared by heating the mixture at 70 °C for 30 min followed by filtration. Around 20 mL of filtrate or algal extract was added (dropwise) in 0.5 M titanium (VI) isopropoxide (TTIP), and the reaction mixture was placed under stirring conditions for a period of 4 h at 60 °C. The solution was further dried at 60 °C for 12 h using an oven and annealed for 2 h at 600 °C. The UV-vis adsorption studies of the particles showed an absorbance peak (327 nm) along with an energy band gap of 3.14 eV. The diffraction peaks for NPs through XRD analysis confirmed the pure tetragonal anatase phase of the particles. The TiO2NPs were sphere-shaped with 50 nm size as seen in Fig. 4. Furthermore, the composite of TiO2NPs with graphene oxide denoted as TiO2-GO was synthesized that showed accumulation of the TiO2NPs along the wrinkles and edges of GO sheets. Vasanth et al. (2022) fabricated TiO2NPs by utilizing Spirulina platensis extract. Initially, 20 mL of the algal extract was mixed with 80 mL of TiO2 (0.01 M) solution that was reacted for 6 h at room temperature under stirring condition. The appearance of a pale yellow color confirmed the successful formation of TiO2NPs. UV-Vis spectral studies of TiO2NPs identified the prominent absorption band at 300  nm. XRD analysis identified crystalline particles with an anatase phase. The SEM images revealed the irregular dispersion of the particles having spherical morphology and also determined the average particle size lying in 90–150 nm range.

162

P. Pandya and S. Ghosh

Fig. 4  SEM images of (a) TiO2NPs, (b) GO and (c) TiO2-GO nanocomposite, and (d) EDX spectra of TiO2-GO nanocomposite. (Reprinted with permission from Sharma et al. (2018). Copyright © 2018 Elsevier Ltd.)

Phytogenesis Various plant-mediated synthesis of nanoparticles are reported as the plants are rich in numerous phytochemicals that serve as reducing and capping agents during nanoparticle synthesis (Shende et al., 2017, 2018; Ghosh et al., 2016a, b). Thakur et al. (2019) fabricated TiO2NPs by employing Azadirachta indica leaf extract and further evaluated their antimicrobial activity. Around 20 g of A. indica leaves was washed and boiled for 30 min in sterile double-distilled water (100 mL) followed by filtration. The mixture of A. indica leaf extract (10 mL) and 90 mL titanium dioxide (5 mM) was heated at 60 °C for 1 h. The resulting TiO2NPs were recovered by centrifugation (7826 × g) for 20 min. SEM images showed the spherical TiO2NPs with sizes ranging from 25 to 87 nm. Likewise, the TEM images showed a smooth spherical structure with 15–45 nm size. The crystalline anatase and rutile phases of NPs (41.9  nm) were confirmed from XRD analysis. The FTIR spectra showed the absorption bands for O-H stretching of alcohols and phenolic (3581.96 cm−1), C=C (1166.92 cm−1), C=O (1091.86 cm−1), and the typical peak of Ti-O-Ti at 709.62 cm−1. The antibacterial activity of TiO2NPs was observed against Salmonella typhi, E. coli, and K. pneumoniae. The lowest MIC value (10.42 μg/mL) against S. typhi and E. coli and the lowest MBC value (83.3 μg/mL) toward K. pneumoniae were detected.

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

163

Aswini et al. (2021) used Ledebouria revoluta bulb extract for the fabrication of TiO2NPs. The mixture of titanium dioxide (5 mM) and plant bulb extract was heated at 50 °C for 4 h followed by centrifugation at 10,000 rpm. UV-vis spectroscopy of the resulting TiO2NPs showed an absorbance peak at 312 nm. The HR-TEM images showed the agglomerated particles with spherical morphology. XRD analysis revealed the rutile phase of NPs (tetragonal structure) along with a mean crystalline size of 47 nm. The absorption peaks of O-H (3275 and 1635 cm−1), C-O (1213 cm−1), C-H (2922  cm−1), NH2 (1062  cm−1), C=O (1535  cm−1), and the typical peak of Ti-O-O were found at 482 cm−1 and 576 cm−1 on FTIR analysis. A 60 μL of TiO2NPs exhibited the highest ZOI against Clostridium tetani (5.3 ± 3.05 mm) followed by Vibrio cholerae (4.16  ±  1.60  mm), Bacillus cereus (4.0  ±  2.0  mm), and E. coli (3.83 ± 1.25 mm). Anbumani et al. (2022) reported Luffa acutangula leaf extract-mediated TiO2NP fabrication. TiO2NPs were synthesized by reacting 80  mL of titanium sulfate (1 mM) solution and 20 mL of leaf extract for 6 h at room temperature under stirring. The successful TiO2NP synthesis was indicated by the conversion of dark green color of the solution to light green. Furthermore, the reaction mixture was centrifuged at 10,000  rpm for 10  min for recovering the phytogenic TiO2NPs. UV-vis spectroscopy revealed the highest peak of absorbance at 322 nm. SEM and TEM analysis identified the hexagonal morphology of the particle with size ranging between 10 and 49  nm as evident from Fig.  5. EDX analysis of NPs confirmed 5.68% and 94.32% of elemental Ti and O, respectively. The XRD spectrum identified intense peaks, which indicated the crystalline nature of along with the rutile phase of the particles. FTIR analysis identified the peaks at 598 cm−1 (alkyl halides), 1132  cm−1 (carboxylic acid), 1381  cm−1 (nitro group), 1611  cm−1 (amines), and

Fig. 5  Characterization analysis (a) and (b) SEM micrograph of synthesized TiO2NPs, (c) energy-­ dispersive X-ray spectroscopy exhibiting the chemical components of the synthesized TiO2NPs, (d–f) transmission electron microscopic analysis of TiO2NPs, and (g) SAED pattern of TiO2NPs. (Reprinted with permission from Anbumani et  al. (2022) Copyright © 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University)

164

P. Pandya and S. Ghosh

3393 cm−1 (phenol). TiO2NPs (40 mg/mL) showed the highest ZOI against E. coli (45  ±  0.21), which was followed by P. aeruginosa (43  ±  0.45  mm), S. aureus (42 ± 0.13 mm), K. pneumoniae (27 ± 0.54 mm), E. faecalis (21 ± 0.41 mm), and B. subtilis (18 ± 0.56 mm). Ahmad et al. (2020) studied the antimicrobial activity of TiO2NPs synthesized using Mentha arvensis leaf extract. The TiO2NPs were fabricated by reacting 20 mL of ethanolic leaf extract and 50 mL of titanium tetraisopropoxide for 5 h at 50 °C under shaking condition. The appearance of whitish brown color suggested the successful synthesis of TiO2NPs that was further recovered by centrifugation at 5000 rpm for 15 min. The recovered nanoparticles were dried at 500 °C for 5 h. The UV-vis spectroscopy determined the specific absorption peak of TiO2NPs at 400 nm. Evenly distributed, smooth, and spherical particles were 20–70 nm in size as determined using SEM. The peaks at 2θ = 25.27° identified using XRD were attributed to the 110 anatase form and indicated the crystalline nature of the phytogenic TiO2NPs. The absorption band of O-Ti-O was observed at 596 cm−1 and 977 cm−1 in FTIR. The bands were also observed at 3371.36 cm−1 (-OH), 1634 cm−1 (C=C), 1145.26  cm−1 (O-H), 13.82.63  cm−1 (C-H), 1124.82  cm−1 (C-O), 1043.94  cm−1 (CO-O-CO), 800.46 cm−1 (C-C), and 626.18 cm−1 showing the vinyl biomolecule vibrations within -CH group. The maximum ZOI for TiO2NPs (30  mg/mL) was against Proteus vulgaris, which was 15 mm, while no inhibition was noted against both E. coli and S. aureus. The antifungal activity at 30 mg/mL TiO2NPs concentration was confirmed by 15 mm ZOI against Aspergillus niger, while no response was observed against Arthrographis cuboid and Aspergillus fumigates. Shimi et al. (2022) used an alternative method for the fabrication of TiO2NPs using mulberry leaf extract. The synthesis began by mixing 1 molar TTIP into 10 mL mulberry leaf extract followed by stirring at 800 rpm at 80 °C. The formation of a milky white precipitate within 30 min indicated the successful fabrication of TiO2NPs. Furthermore, the reaction mixture was centrifuged at 15000  rpm for 10 min followed by drying at 100 °C for 1 h. The highest absorbance at 398 nm was evaluated from the UV-vis spectroscopy. The spherical and conjoint spherical structures of around 24 nm were identified by FE-SEM. Elemental Ti (30.46%) and O (69.54%) were confirmed from EDX analysis. TiO2NPs with 22 nm mean crystalline size along with the anatase phase were detected by XRD analysis. The FTIR analysis showed intense absorption peaks at 2933  cm−1 and 2850  cm−1 (C-H), 1633 cm−1 and 3428 cm−1 (OH), and 1380 cm−1 (representing C-C bond stretching, plant biocompounds, and C-O bond stretching). The O-Ti-O bonding occurring in the cationic anatase phase was identified from the peak obtained at 686 cm−1. The kinetic study revealed the pseudo-first-order model as the best-fitted model in explaining the absorption process. TiO2NPs showed an effective response toward S. aureus. In another study, Vijayakumar et al. (2020) reported the formation of TiO2NPs using Ocimum americanum leaf extract. The TiO2NPs were synthesized by adding 10  mL of plant leaf extract to titanium oxysulfate (0.5  M) solution followed by 30 min stirring at 60 °C. The pH of the reaction mixture was adjusted to 8 by using

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

165

1 M NaOH. The precipitate was recovered and washed followed by calcinations at 800 °C for 3 h. UV-vis spectroscopy revealed the maximum absorbance at 334 nm. FE-SEM images showed spherical TiO2NPs with a size of 25  nm, while EDAX analysis confirmed 67.45% of TiO2 in the fabricated NPs. XRD analysis showed a 21.4  nm wurtzite crystalline structure of TiO2NPs. FTIR analysis identified the absorption peaks at 2951 cm−1 (C-H), 2921 cm−1 (C=C), and 1383 cm−1 (C=C, rock alkenes). The effective inhibition was observed against B. cereus (36 ± 1.08 mm), Salmonella paratyphi (28 ± 2.06 mm), Clostridium perfringens (23 ± 1.52 mm), and K. pneumoniae (21  ±  1.82  mm). Similarly, the antifungal activity was confirmed by the highest ZOI against C. albicans (30  ±  0.84  mm) and A. niger (22 ± 1.20 mm). Amanulla and Sundaram (2019) derived TiO2NPs from orange peel extract. Initially, titanium tetrachloride (1 M) was mixed in deionized ice (100 mL) followed by the addition of orange peel extract (10 mL). The components were allowed to react for 3  h under stirring condition, and the mixture was washed constantly to adjust the pH to 7. The resulting TiO2NPs were filtered, washed, and dried at 100 °C for 10 h followed by calcinations at 500 °C for 4 h. The appearance of dark brown color powder after calcination indicated the disintegration of carboxylic groups, glucose, furfural, and residues of insoluble polysaccharides that existed in the orange peel extract. TiO2NPs showed a distinct absorbance peak at 315 nm in its UV-vis spectra, and the band gap energy was 2.52 eV. The humidity sensing measurements indicated the highest sensitivity factor Sf = 4089 with a 45 s of response time and 197  s of recovery time. SEM images showed a highly porous angular morphology of TiO2NPs with sizes ranging from 20 to 50  nm. XRD analysis revealed the anatase phase of the TiO2NPs along with 17.30 nm of crystalline size. FTIR analysis identified the absorbance bands at 3420 cm−1 and 1642 cm−1 attributing to water molecules present on the surface of the TiO2NPs, apart from bands at 2349 and 2930 cm−1 (C=O and N-H), 1050 and 1391 cm−1 (CO and C=C), and less than 700 cm−1 that were mainly attributed to Ti-O-Ti bond. At 50 mg/mL concentration of TiO2NPs, a greater antibacterial activity was noted against P. aeruginosa followed by S. aureus and E. coli that showed ZOI of 14 mm, 12 mm, and 9 mm, respectively. Hunagund et al. (2016) fabricated TiO2NPs using Piper betel leaf extract. The TiO2NPs were synthesized by adding 0.5 mL of titanium (IV) n-butoxide (TNB) to the leaf extract followed by 45  min of mixing. After autoclaving at 180  °C for 180 min, the resulting TiO2NPs were recovered by centrifugation followed by washing with distilled water and ethanol. The final brown-colored product was obtained after drying at 50 °C for 60 min. UV-vis spectroscopy showed a maximum absorption peak at 342 nm. The XRD analysis identified the strong and sharp peaks, which indicated the crystalline nature along with the rutile phase and tetragonal structure of the particles. The FTIR analysis revealed the peak for Ti-O at 530 cm−1, which confirmed TiO2NP formation. The disappearance of 1740 cm−1 peak and alteration in 3442 cm−1 peak, 1623 cm−1 to 1024 cm−1, indicated that the biomolecules present in plant leaf extracts such as carbohydrates, tannins, polyols, proteins, and flavonoids possessing C=O group (1740  cm−1) might have played noteworthy role in

166

P. Pandya and S. Ghosh

stabilization and bioreduction of TiO2NPs. TEM micrographs revealed the spherical particles with 8 nm mean particle size. The elemental analysis of the particles confirmed the existence of Ti and O elements along with the C and N, which might be attributed to the presence of the protein and carbohydrate residues. Higher antibacterial activity of the phytogenic TiO2NPs was noted against S. aureus and E. coli with ZOI of 11 mm and 10 mm, respectively, while the MIC value was 25 μg/mL. In another study, Manikandan et  al. (2018) described the green synthesis of TiO2NPs from Prunus yedoensis leaf extract (PYLE). The synthesis of TiO2NPs was initiated by adding 50 mL titanium dioxide (0.1 M) dropwise to the hot 50 mL PYLE (1:1 ratio) under 12 h of stirring conditions at 80 °C. The solution was further calcinated at 500 °C for 1 h in a muffle furnace. The absorption peaks in the spectral range of 220–410 nm were observed in UV-vis spectra. The synthesis of TiO2NPs was dependent on the method employed in the production and the temperature used in the calcination, which was confirmed by different peaks in the XRD showing the rutile and anatase phases of the particles. The FTIR spectra indicated the peak at 655 cm−1 (Ti-O stretching), which confirmed the formation of TiO2NPs. The shifting of bands attributed to the stretching and bending vibration of C–H bonds from the residual butyl group (1082 and 1377 cm−1), at 1626 cm−1 (O–H stretching vibration of absorbed water molecules), and shifting of 3411 cm−1 corresponded to -O-H stretching vibration. The purity of the particles was confirmed by X-ray photoelectron spectroscopy (XPS), which showed the binding energies of 463.23 and 457.20 eV attributing to the electrons of Ti and O. The HRTEM showed that the particles were spherical with smooth edges, while the size ranged between 25 and 50 nm. The antibacterial activity of the TiO2NPs was tested against S. aureus and E. coli, which showed a ZOI of 6  mm and 5  mm, respectively, at 200  μg/mL concentration. Subhapriya and Gomathipriya (2018) reported TiO2NPs with antimicrobial activity that was fabricated using Trigonella foenum-graecum (TF) leaf extract. The TiO2NPs were prepared by mixing 15 mL leaf extract with titanium oxysulfate solution (0.5 M) followed by 15 min of stirring. The pH of the reaction mixture was adjusted to 8 with 1 M NaOH. Furthermore, the precipitates obtained were washed repeatedly with the deionized water followed by filtration and calcinations at 700 °C for 3  h. The absorption peak of TiO2NPs was obtained at 400  nm in the UV-vis spectra. The HRTEM images revealed the aggregated spherical TiO2NPs of size ranging from 20 to 90  nm. XRD analysis revealed the crystalline structure of TiO2NPs with 30–25 nm mean particle size and the peak obtained at 2θ = 25.28° was corresponded to 101 of anatase form. FTIR analysis identified the peak of Ti-O-Ti located below 1200 cm−1, at 598 and 975 cm−1 that was attributed to O-Ti-O bond, and the peaks of hydroxyl and water stretching vibrations were noted at 3475 cm−1 and 1630 cm−1, respectively. The TiO2NPs exhibited an effective antimicrobial activity against Yersinia enterocolitica, S. aureus, E. coli, Streptococcus faecalis, and E. faecalis, the ZOI for which were 10.6  mm, 11.2  mm, 10.8  mm, 11.6 mm, and 11.4 mm, respectively.

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

167

Antiviral Perspectives There is a dearth of scientific studies on the exploration of the antiviral efficiencies of the biogenic TiO2NPs. However, there is tremendous potential in developing antiviral therapeutics as evident from the recent literature on the applications of chemically synthesized TiO2NPs. Acuña-Fuentes et  al. (2022) evaluated the antiviral effect of TiO2NPs against tobacco mosaic virus (TMV) in Capsicum annuum L as shown in Fig. 6. Initially, the plant was germinated and transferred to 9-L bags containing tezontle substrate, humus, and soil (in the ratio of 2:2:5) after the formation of six to eight true leaves. About 90% stainer solution was used as the source of the plant nutrition, and the experiment was performed at 21.3 °C in a greenhouse with relative humidity (RH) of 59%. In the sol-gel method of TiO2NP synthesis, 5 mL of 97% titanium isopropoxide and 100 mL of 99.5% 2-propanol were mixed and agitated followed by the addition of 30 mL water and stirring for 24 h. The solid product recovered after the completion of the reaction was filtered, washed, and dried at room temperature. Afterward, it was subjected to 18 h of muffle drying at 110 °C and was further calcinated for 4 h at 500 °C. The artificial infection of TMV to the experimental plants was carried out by adding a 1:10 mixture of infected material and extraction buffer (GEB). The hemispherical shape with the size of 20 nm for the fabricated TiO2NPs was identified from the SEM images. The aggregated NPs

Fig. 6 TiO2NPs at a scale of 500 nm (a) and 100 nm (b); absorption and distribution of TiO2NPs in leaves of C. annuum (c, d). (Reprinted from Acuña-Fuentes et al. (2022))

168

P. Pandya and S. Ghosh

having irregular morphology and a size of 0.6 microns formed interstitial voids. XRD analysis suggested the anatase phase of the TiO2NPs along with a few brookite phase particles. The weight percentage and mean crystal size of phases were 91% and 11.6 nm, respectively, for the anatase phase and 9% and 13.5 nm, respectively, for the brookite phase. The TiO2NP-treated infected plants showed enhancement in the height of the plant (122%) compared to the untreated infected plant. A decrease in the symptoms caused by the virus was observed in the infected plants treated with 150 and 250 μg/mL TiO2NPs compared to the control. It is interesting to note that about 90% reduction in the viral concentration was observed upon treatment with 150 and 200 μg/mL TiO2NPs. Khaiboullina et al. (2020) explored the inactivation ability of TiO2NPs for human coronavirus strain NL63 (HCoV-NL63) via coatings and UVC radiations. Firstly, in order to prepare TiO2NP-coated glass coverslips, around 300 μg/mL of particle suspension was prepared using deionized water followed by vortexing. Subsequently, 600 μL TiO2NPs were placed on the UV-treated glass coverslip followed by drying at 60 °C that resulted in the formation of a semi-transparent coating. The efficacy of TiO2NPs in enhancing the inactivation of HCoV-NL63 upon UV exposure was evaluated by placing the coverslip in the center of a 60-mm culture dish. An aliquot of the virus was applied to the coverslip followed by UV exposure for the selected time period after which the inactivation of the virus was evaluated. Within 1 min of UV exposure, a significant reduction in the amount of intact viral genomic RNA was observed. On increasing the exposure time to 5, 10, and 30 min, complete degradation was observed along with regions coding for spike proteins. It was observed from the experiment that the samples exposed to UV for 5 min and above did not possess any intracellular viral genome, thus suggesting their complete inactivation. The mechanism is illustrated in Fig. 7. León-Gutiérrez et  al. (2021) investigated the effect of secondary metabolites implanted into a carrier of functionalized titanium dioxide nanoparticles denoted by

Fig. 7  Schematic illustration of photocatalytic inactivation of HCoV-NL63 principle. Irradiation with UV light generates a specific “electron-hole (e−-h+)” pair, and reactive oxygen species (ROS), including hydroxyl and superoxide radicals on the surface of TiO2NPs. These ROS have strong oxidative ability, which can inactivate viruses through oxidative damage. (Reprinted from Khaiboullina et al. (2020))

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

169

SMNP against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Firstly, an inorganic metal oxide carrier was used for the development of an organic nano-compound, which was further functionalized via impregnation followed by dispersion in the extract containing secondary metabolites derived from citrus. This process was carried out under temperature-controlled conditions in order to stabilize interactions and the formation of 2- to 5 nm-sized particles. The efficacy analysis of SMNP over SARS-CoV-2 showed about 750-fold faster tissue damage compared to the plates containing VERO E6 cells preincubated with SMNP.  At 100% SMNP concentration, the viability of MDCK cells was reduced only by 5.5% after exposure for 10 min showing their biocompatibility to healthy cells. However, upon treatment of healthy canine kidney MDCK cell culture for 10 min with glutaraldehyde, around 59% and 23% cell death at chlorine concentration equivalent to 4% and 0.25%, respectively. Similarly, at 1% and 0.062% chlorhexidine treatment, about 79% and 32% cell death were observed, respectively. Thus, SMNP showed effective inhibition against SARS-CoV-2 viral replication under in vitro conditions and demonstrated minimum cytotoxicity toward healthy cells. Repkova et al. (2017) studied the inhibition of replication in H5N1 influenza A virus with the use of deoxyribozymes (Dz) non-covalently immobilized on TiO2NP-­ polylysine (TiO2.PL) nanocomposite that was denoted as (TiO2.PL).Dz. The fabrication of TiO2NPs was carried out from the titanium tetrachloride (TiCl4) after which the aqueous solution of PL was added to the TiO2NPs followed by 30 min of stirring. The resulting reaction mixture was washed and resuspended in 0.1 M NaCl. The concentration of TiO2.PL conjugates obtained were around 1 mg/mL for the particles and about 1  μmol/mg for the amino groups of PL.  After the successful formation of nanoconjugates, 20 μL Dz solution was added to it followed by 30 min of stirring, which resulted in the formation of (TiO2.PL).Dz suspensions. Three different suspensions according to the form of TiO2 (amorphous (Amf), brookite (Brt), and anatase (Ans)) were obtained such as (Amf.PL).Dz, (Brt.PL).Dz, and (Ans.PL).Dz, respectively, which were further centrifuged, washed (0.1 M NaCl), and resuspended. About less than 10–15% of the immobilized Dz was lost due to the washing of nanocomposites with 1 M NaCl, saline buffer, and hot water (90 °C). Dz 10-23 enzyme catalyzed the cleavage of RNA at A-U positions. Upon evaluating the RNA cleavage ability of (TiO2.PL).Dz nanocomposite in the cell-free system, a resulting 13-mer product was obtained. Thus, the retention of RNA cleavage ability of Dz even after the nanocomposite formation was confirmed. The highest viral replication inhibition efficiency of 99.96% was achieved upon employing (Ans.PL).Dz nanocomposite at the lowest concentration of Dz (0.1 μM).

Future Perspectives Biogenic synthesis offers an environmentally benign, rapid, cost-effective, and efficient route for the fabrication of TiO2NPs with various applications. There is a scope to increase the efficiency of the process by selecting appropriate biological templates, such as microbes, plants, and/or their purified compounds. Likewise, various

170

P. Pandya and S. Ghosh

reaction parameters, such as metal salt concentration, extract concentration, temperature, pH, and duration of the reaction, can be optimized to get monodispersed TiO2NPs (Adersh et al., 2015). Various other metals can be doped in the biogenic TiO2NPs for enhancing their therapeutic and photocatalytic properties (Robkhob et al., 2020; Karmakar et al., 2020). Apart from antimicrobial applications, the role of biogenic can be explored for tissue regeneration and repair applications. The particles can be incorporated into polymeric scaffolds to impart strength and biocompatibility, which are ideal for developing implants (Ghosh & Webster, 2021b). Bioactive principles from medicinal plants, drugs, targeting ligands, and other small molecules can be attached to the surface of the biogenic TiO2NPs for targeted delivery of the drugs and induction of cellular uptake (Kitture et al., 2015). Hence, there is a wide scope for developing highly efficient nanomedicine using biogenic TiO2NPs.

Conclusion The TiO2NPs can be successfully synthesized from different sources such as bacteria, fungi, algae, and plants. The biologically synthesized TiO2NPs are biocompatible and can be used for various therapeutic applications. This method is advantageous to chemical and physical synthesis as it does not involve any toxic chemicals as reducing or capping agents. Thorough optimization of the reaction parameters may help in tuning the size and shape of the biologically synthesized TiO2NPs. Various interdisciplinary approaches by integrating genomics, metabolomics, and proteomics can help to identify the exact mechanism behind the synthesis of TiO2NPs by the microbes. Furthermore, the microbes can be genetically engineered for better synthesis of TiO2NPs. The antiviral activity of biologically synthesized TiO2NPs was not reported till date, so there is a vast scope in exploring the antiviral activities of biologically synthesized TiO2NPs against different viruses that cause harmful diseases in animals and plants. However, toxicity studies should be carried out before the biogenic TiO2NPs can be used as candidate nanomedicine in future. Acknowledgment  Mr. Pranav Jayesh Pandya is thankful to the Council of Scientific and Industrial Research (CSIR, Government of India) for the Junior Research Fellowship (JRF) (09/1371(15459)/2022-EMR-I).

References Acuña-Fuentes, N.  L., Vargas-Hernandez, M., Rivero-Montejo, S.  D. J., Rivas-Ramirez, L.  K., Macias-Bobadilla, I., Palos-Barba, V., Rivera-Muñoz, E.  M., Guevara-Gonzalez, R.  G., & Torres-Pacheco, I. (2022). Antiviral activity of TiO2 NPs against tobacco mosaic virus in chili pepper (Capsicum annuum L.). Agriculture, 12(12), 2101. Adersh, A., Kulkarni, A. R., Ghosh, S., More, P., Chopade, B. A., & Gandhi, M. N. (2015). Surface defect rich ZnO quantum dots as antioxidant inhibiting α-amylase and α-glucosidase: A potential anti-diabetic nanomedicine. Journal of Materials Chemistry B, 3(22), 4597–4606.

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

171

Ağçeli, G. K., Hammachi, H., Kodal, S. P., Cihangir, N., & Aksu, Z. (2020). A novel approach to synthesize TiO2 nanoparticles: Biosynthesis by using Streptomyces sp. HC1. Journal of Inorganic and Organometallic Polymers and Materials, 30, 3221–3229. Ahmad, W., Jaiswal, K. K., & Soni, S. (2020). Green synthesis of titanium dioxide (TiO2) nanoparticles by using Mentha arvensis leaves extract and its antimicrobial properties. Inorganic and Nano-Metal Chemistry, 50(10), 1032–1038. Amanulla, A. M., & Sundaram, R. J. M. T. P. (2019). Green synthesis of TiO2 nanoparticles using orange peel extract for antibacterial, cytotoxicity and humidity sensor applications. Materials Today: Proceedings, 8, 323–331. Anbumani, D., Vizhi Dhandapani, K., Manoharan, J., Babujanarthanam, R., Bashir, A.  K. H., Muthusamy, K., & Kanimozhi, K. (2022). Green synthesis and antimicrobial efficacy of titanium dioxide nanoparticles using Luffa acutangula leaf extract. Journal of King Saud University-Science, 34(3), 101896. Arya, S., Sonawane, H., Math, S., Tambade, P., Chaskar, M., & Shinde, D. (2021). Biogenic titanium nanoparticles (TiO2 NPs) from Tricoderma citrinoviride extract: Synthesis, characterization and antibacterial activity against extremely drug-resistant Pseudomonas aeruginosa. International Nano Letters, 11, 35–42. Aslam, M., Abdullah, A. Z., & Rafatullah, M. (2021). Recent development in the green synthesis of titanium dioxide nanoparticles using plant-based biomolecules for environmental and antimicrobial applications. Journal of Industrial and Engineering Chemistry, 98, 1–16. Aswini, R., Murugesan, S., & Kannan, K. (2021). Bio-engineered TiO2 nanoparticles using Ledebouria revoluta extract: Larvicidal, histopathological, antibacterial and anticancer activity. International Journal of Environmental Analytical Chemistry, 101(15), 2926–2936. Blecher, K., Nasir, A., & Friedman, A. (2011). The growing role of nanotechnology in combating infectious disease. Virulence, 2(5), 395–401. Bloch, K., Pardesi, K., Satriano, C., & Ghosh, S. (2021). Bacteriogenic platinum nanoparticles for application in nanomedicine. Frontiers in Chemistry, 9, 624344. Buazar, F., Baghlani-Nejazd, M. H., Badri, M., Kashisaz, M., Khaledi-Nasab, A., & Kroushawi, F. (2016). Facile one-pot phytosynthesis of magnetic nanoparticles using potato extract and their catalytic activity. Starch-Stärke, 68(7–8), 796–804. Dastjerdi, R., & Montazer, M. (2010). A review on the application of inorganic nano-structured materials in the modification of textiles: Focus on anti-microbial properties. Colloids and Surfaces, B: Biointerfaces, 79(1), 5–18. Dizaj, S.  M., Lotfipour, F., Barzegar-Jalali, M., Zarrintan, M.  H., & Adibkia, K. (2014). Antimicrobial activity of the metals and metal oxide nanoparticles. Materials Science and Engineering: C, 44, 278–284. Drummer, S., Madzimbamuto, T., & Chowdhury, M. (2021). Green synthesis of transition-metal nanoparticles and their oxides: A review. Materials, 14(11), 2700. Gami, B., Bloch, K., Mohammed, S. M., Karmakar, S., Shukla, S., Asok, A., Thongmee, S., & Ghosh, S. (2022). Leucophyllum frutescens mediated synthesis of silver and gold nanoparticles for catalytic dye degradation. Frontiers in Chemistry, 10, 932416. Ghosh, S. (2018). Copper and palladium nanostructures: A bacteriogenic approach. Applied Microbiology and Biotechnology, 101, 7693–7701. Ghosh, S., & Webster, T. J. (2021a). Nanobiotechnology: Microbes and plant assisted synthesis of nanoparticles, mechanisms and applications. Elsevier Inc. eBook ISBN: 978-0-12-823115-9; Paperback ISBN: 978-0-12-822878-4. Ghosh, S., & Webster, T. J. (2021b). Mesoporous silica based nanostructures for bone tissue regeneration. Front Mater, 8, 692309. Ghosh, S., Chacko, M. J., Harke, A. N., Gurav, S. P., Joshi, K. A., Dhepe, A., Kulkarni, A. S., Shinde, V. S., Parihar, V. S., Asok, A., & Banerjee, K. (2016a). Barleria prionitis leaf mediated synthesis of silver and gold nanocatalysts. Journal of Nanomedicine & Nanotechnology, 7(4), 394.

172

P. Pandya and S. Ghosh

Ghosh, S., Gurav, S.  P., Harke, A.  N., Chacko, M.  J., Joshi, K.  A., Dhepe, A., Charolkar, C., Shinde, V.  S., Kitture, R., Parihar, V.  S., Banerjee, K., Kamble, N., Bellare, J., & Chopade, B. A. (2016b). Dioscorea oppositifolia mediated synthesis of gold and silver nanoparticles with catalytic activity. Journal of Nanomedicine & Nanotechnology, 7(5), 1000398. Guo, Y., Ma, L., Mao, K., Ju, M., Bai, Y., Zhao, J., & Zeng, X. C. (2019). Eighteen functional monolayer metal oxides: Wide bandgap semiconductors with superior oxidation resistance and ultrahigh carrier mobility. Nanoscale Horizons, 4(3), 592–600. Hemalatha, K., Madhumitha, G., Kajbafvala, A., Anupama, N., Sompalle, R., & Roopan, S.  M. (2013). Function of nanocatalyst in chemistry of organic compounds revolution: An overview. Journal of Nanomaterials, 2013, 4. Hunagund, S.  M., Desai, V.  R., Kadadevarmath, J.  S., Barretto, D.  A., Vootla, S., & Sidarai, A.  H. (2016). Biogenic and chemogenic synthesis of TiO2 NPs via hydrothermal route and their antibacterial activities. RSC Advances, 6(99), 97438–97444. Iravani, S. (2011). Green synthesis of metal nanoparticles using plants. Green Chemistry, 13(10), 2638–2650. Jadoun, S., Arif, R., Jangid, N. K., & Meena, R. K. (2021). Green synthesis of nanoparticles using plant extracts: A review. Environmental Chemistry Letters, 19, 355–374. Jayaseelan, C., Rahuman, A.  A., Roopan, S.  M., Kirthi, A.  V., Venkatesan, J., Kim, S.  K., Iyappan, M., & Siva, C. (2013). Biological approach to synthesize TiO2 nanoparticles using Aeromonas hydrophila and its antibacterial activity. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy, 107, 82–89. Karmakar, S., Ghosh, S., & Kumbhakar, P. (2020). Enhanced sunlight driven photocatalytic and antibacterial activity of flower-like ZnO@MoS2 nanocomposite. Journal of Nanoparticle Research, 22, 11. Khaiboullina, S., Uppal, T., Dhabarde, N., Subramanian, V. R., & Verma, S. C. (2020). Inactivation of human coronavirus by titania nanoparticle coatings and UVC radiation: Throwing light on SARS-CoV-2. Viruses, 13(1), 19. Kitture, R., Ghosh, S., More, P. A., Gaware, S., Datar, S., Chopade, B. A., & Kale, S. N. (2015). Curcumin-loaded, self-assembled aloe vera template for superior antioxidant activity and trans-membrane drug release. Journal of Nanoscience and Nanotechnology, 15(6), 4039–4045. Kubacka, A., Diez, M. S., Rojo, D., Bargiela, R., Ciordia, S., Zapico, I., Albar, J. P., Barbas, C., Martins dos Santos, V. A., Fernández-García, M., & Ferrer, M. (2014). Understanding the antimicrobial mechanism of TiO2-based nanocomposite films in a pathogenic bacterium. Scientific Reports, 4(1), 4134. Lazar, M. A., Varghese, S., & Nair, S. S. (2012). Photocatalytic water treatment by titanium dioxide: Recent updates. Catalysts, 2(4), 572–601. León-Gutiérrez, G., Cabello-Gutiérrez, C., Martínez-Gómez, M.  H., Azuara, P., Madden, B., Shalkow, J., & Mejía, A. (2021). Secondary metabolites in functionalized titanium dioxide (TIO2) nanoparticles: A novel and safe virucide against SARS-CoV-2. Journal of Nano Research, 70, 137–145. Lingaraju, K., Basavaraj, R. B., Jayanna, K., Bhavana, S., Devaraja, S., Swamy, H. K., Nagaraju, G., Nagabhushana, H., & Naika, H.  R. (2021). Biocompatible fabrication of TiO2 nanoparticles: Antimicrobial, anticoagulant, antiplatelet, direct hemolytic and cytotoxicity properties. Inorganic Chemistry Communications, 127, 108505. Manikandan, V., Velmurugan, P., Jayanthi, P., Park, J.  H., Chang, W.  S., Park, Y.  J., & Oh, B.  T. (2018). Biogenic synthesis from Prunus× yedoensis leaf extract, characterization, and photocatalytic and antibacterial activity of TiO2 nanoparticles. Research on Chemical Intermediates, 44, 2489–2502. Meenatchisundaram, N., Chellamuthu, J., Jeyaraman, A. R., Arjunan, N., Muthuramalingam, J. B., & Karuppuchamy, S. (2022). Biosynthesized TiO2 nanoparticles an efficient biogenic material for photocatalytic and antibacterial applications. Energy & Environment, 33(2), 377–398. Mittal, A. K., Chisti, Y., & Banerjee, U. C. (2013). Synthesis of metallic nanoparticles using plant extracts. Biotechnology Advances, 31(2), 346–356.

Biogenic TiO2 Nanoparticles for Advanced Antimicrobial and Antiviral…

173

Moradpoor, H., Safaei, M., Golshah, A., Mozaffari, H. R., Sharifi, R., Imani, M. M., & Mobarakeh, M. S. (2021). Green synthesis and antifungal effect of titanium dioxide nanoparticles on oral Candida albicans pathogen. Inorganic Chemistry Communications, 130, 108748. Nabi, G., Khalid, N. R., Tahir, M. B., Rafique, M., Rizwan, M., Hussain, S., Iqbal, T., & Majid, A. (2018). A review on novel eco-friendly green approach to synthesis TiO2 nanoparticles using different extracts. Journal of Inorganic and Organometallic Polymers and Materials, 28, 1552–1564. Nadeem, M., Tungmunnithum, D., Hano, C., Abbasi, B. H., Hashmi, S. S., Ahmad, W., & Zahir, A. (2018). The current trends in the green syntheses of titanium oxide nanoparticles and their applications. Green Chemistry Letters and Reviews, 11(4), 492–502. Nohynek, G.  J., Lademann, J., Ribaud, C., & Roberts, M.  S. (2007). Grey goo on the skin? Nanotechnology, cosmetic and sunscreen safety. Critical Reviews in Toxicology, 37(3), 251–277. Órdenes-Aenishanslins, N. A., Saona, L. A., Durán-Toro, V. M., Monrás, J. P., Bravo, D. M., & Pérez-Donoso, J. M. (2014). Use of titanium dioxide nanoparticles biosynthesized by Bacillus mycoides in quantum dot sensitized solar cells. Microbial Cell Factories, 13, 90. Piccinno, F., Gottschalk, F., Seeger, S., & Nowack, B. (2012). Industrial production quantities and uses of ten engineered nanomaterials in Europe and the world. Journal of Nanoparticle Research, 14, 1109. Rajakumar, G., Rahuman, A. A., Roopan, S. M., Khanna, V. G., Elango, G., Kamaraj, C., Zahir, A. A., & Velayutham, K. (2012). Fungus-mediated biosynthesis and characterization of TiO2 nanoparticles and their activity against pathogenic bacteria. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy, 91, 23–29. Rehman, S., Farooq, R., Jermy, R., Mousa Asiri, S., Ravinayagam, V., Al Jindan, R., Alsalem, Z., Shah, M. A., Reshi, Z., Sabit, H., & Alam Khan, F. (2020a). A wild Fomes fomentarius for biomediation of one pot synthesis of titanium oxide and silver nanoparticles for antibacterial and anticancer application. Biomolecules, 10(4), 622. Rehman, S., Jermy, R., Asiri, S. M., Shah, M. A., Farooq, R., Ravinayagam, V., Ansari, M. A., Alsalem, Z., Al Jindan, R., Reshi, Z., & Khan, F. A. (2020b). Using Fomitopsis pinicola for bioinspired synthesis of titanium dioxide and silver nanoparticles, targeting biomedical applications. RSC Advances, 10(53), 32137–32147. Repkova, M., Levina, A., Chelobanov, B., Ismagilov, Z., Shatskaya, N., Baiborodin, S., Filippova, E., Mazurkova, N., & Zarytova, V. (2017). Efficient inhibition of influenza A viral replication in cells by deoxyribozymes delivered by nanocomposites. International Journal of Antimicrobial Agents, 49(6), 703–708. https://doi.org/10.1016/j.ijantimicag.2017.01.026 Robkhob, P., Ghosh, S., Bellare, J., Jamdade, D., Tang, I.  M., & Thongmee, S. (2020). Effect of silver doping on antidiabetic and antioxidant potential of ZnO nanorods. Journal of Trace Elements in Medicine and Biology, 58, 126448. Roopan, S. M., & Khan, M. A. (2021). MoS2 based ternary composites: Review on heterogeneous materials as catalyst for photocatalytic degradation. Catalysis Reviews, 27, 1–74. Sagadevan, S., Imteyaz, S., Murugan, B., Lett, J. A., Sridewi, N., Weldegebrieal, G. K., Fatimah, I., & Oh, W. C. (2022). A comprehensive review on green synthesis of titanium dioxide nanoparticles and their diverse biomedical applications. Green Processing and Synthesis, 11(1), 44–63. Santos, C. S., Gabriel, B., Blanchy, M., Menes, O., García, D., Blanco, M., Arconada, N., & Neto, V. (2015). Industrial applications of nanoparticles–A prospective overview. Materials Today: Proceedings, 2(1), 456–465. Sharma, M., Behl, K., Nigam, S., & Joshi, M. (2018). TiO2-GO nanocomposite for energy and environmental applications: A green synthesis approach. Vacuum, 156, 434–439. Shende, S., Joshi, K. A., Kulkarni, A. S., Shinde, V. S., Parihar, V. S., Kitture, R., Banerjee, K., Kamble, N., Bellare, J., & Ghosh, S. (2017). Litchi chinensis peel: A novel source for synthesis of gold and silver nanocatalysts. Global Journal of Nanomedicine, 3(1), 555603. Shende, S., Joshi, K.  A., Kulkarni, A.  S., Charolkar, C., Shinde, V.  S., Parihar, V.  S., Kitture, R., Banerjee, K., Kamble, N., Bellare, J., & Ghosh, S. (2018). Platanus orientalis leaf mediated rapid synthesis of catalytic gold and silver nanoparticles. Journal of Nanomedicine & Nanotechnology, 9(2), 494.

174

P. Pandya and S. Ghosh

Shimi, A. K., Ahmed, H. M., Wahab, M., Katheria, S., Wabaidur, S. M., Eldesoky, G. E., & Rane, K.  P. (2022). Synthesis and applications of green synthesized TiO2 nanoparticles for photocatalytic dye degradation and antibacterial activity. Journal of Nanomaterials, 2022, 7060388. Subhapriya, S., & Gomathipriya, P. (2018). Green synthesis of titanium dioxide (TiO2) nanoparticles by Trigonella foenum-graecum extract and its antimicrobial properties. Microbial Pathogenesis, 116, 215–220. Thakur, B.  K., Kumar, A., & Kumar, D. (2019). Green synthesis of titanium dioxide nanoparticles using Azadirachta indica leaf extract and evaluation of their antibacterial activity. South African Journal of Botany, 124, 223–227. Vasanth, V., Murugesh, K. A., & Susikaran, S. (2022). Synthesis of titanium dioxide nanoparticles using Spirulina platensis algae extract. The Pharma Innovation, 11(7), 266–269. Vijayakumar, S., Vidhya, E., Anand, G.  C., Nilavukkarasi, M., Punitha, V.  N., & Sakthivel, B. (2020). Eco friendly synthesis of TiO2 nanoparticles using aqueous Ocimum americanum L. leaf extracts and their antimicrobial, anti-proliferative and photocatalytic activities. Vegetos, 33, 805–810. Wang, Z., Haidry, A.  A., Xie, L., Zavabeti, A., Li, Z., Yin, W., Fomekong, R.  L., & Saruhan, B. (2020). Acetone sensing applications of Ag modified TiO2 porous nanoparticles synthesized via facile hydrothermal method. Applied Surface Science, 533, 147383. Zhang, W., Li, Y., Su, Y., Mao, K., & Wang, Q. (2012). Effect of water composition on TiO2 photocatalytic removal of endocrine disrupting compounds (EDCs) and estrogenic activity from secondary effluent. Journal of Hazardous Materials, 215-216, 252–258.

Cerium Oxide Nanoparticles for Biomedical Applications Arumugam Vijayan, Shalini Ramadoss, Natarajan Sisubalan, Muniraj Gnanaraj, Karthikeyan Chandrasekaran, and Varaprasad Kokkarachedu

Overviews Nanotechnology has revolutionized various fields, including biomedicine, by providing innovative solutions for diagnostics, therapeutics, and biomedical research. Cerium oxide (CeO2) nanoparticles have emerged as a promising nanomaterial with diverse applications in the biomedical field. This overview aims to provide insights

A. Vijayan Department of Microbiology, SRM Institute of Science and Technology, Tiruchirappalli Campus, Tiruchirappalli, TN, India S. Ramadoss Department of Botany, Bishop Heber College (Autonomous), Affi. to Bharathidasan University, Trichy, TN, India N. Sisubalan (*) Department of Botany, Bishop Heber College (Autonomous), Affi. to Bharathidasan University, Trichy, TN, India Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy Chiang Mai University, Chiang Mai, Thailand M. Gnanaraj Department of Biotechnology and Bioinformatics, Bishop Heber College (Autonomous), Tiruchirappalli, TN, India K. Chandrasekaran Department of Chemical and Biochemical Engineering, Dongguk University, Seoul, Republic of Korea V. Kokkarachedu Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepciόn, Chile © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_8

175

176

A. Vijayan et al.

into the utilization of CeO2 nanoparticles for biomedical applications, highlighting their properties, synthesis methods, and potential advantages. CeO2 nanoparticles exhibit unique physicochemical properties that make them suitable for biomedical applications. Some key properties of CeO2 nanoparticles include their high surface-­ to-­volume ratio, excellent catalytic activity, redox potential, and oxygen storage capacity. These properties allow CeO2 nanoparticles to participate in various biological processes, such as scavenging reactive oxygen species (ROS), modulating oxidative stress, and promoting tissue regeneration. Synthesis methods for CeO2 nanoparticles involve both physical and chemical approaches. Physical methods include techniques like laser ablation, thermal decomposition, and solgel synthesis, while chemical methods involve precipitation, hydrothermal synthesis, and microwave-assisted synthesis. These methods allow for control over particle size, shape, and surface characteristics, enabling the customization of CeO2 nanoparticles for specific biomedical applications (Ioannou et al., 2023). CeO2 nanoparticles have shown promise in several biomedical applications due to their unique properties: (a) antioxidant and cytoprotective effects: CeO2 nanoparticles possess potent antioxidant properties by acting as ROS scavengers. They can neutralize excessive ROS and protect cells and tissues from oxidative damage. This makes them valuable in treating oxidative stress-related conditions, including neurodegenerative disorders and cardiovascular diseases. (b) Drug delivery systems: CeO2 nanoparticles can be utilized as drug carriers for controlled and targeted drug delivery. Their high surface area and surface chemistry allow for efficient loading and release of therapeutic agents, enhancing drug efficacy and reducing side effects. (c) Tissue engineering and regeneration: CeO2 nanoparticles can promote tissue regeneration by modulating cellular signaling pathways, stimulating cell proliferation, and enhancing angiogenesis. They have potential applications in bone tissue engineering, wound healing, and regenerative medicine. (d) Imaging and diagnostics: CeO2 nanoparticles can be functionalized with imaging agents, such as fluorescent dyes or contrast agents, for various imaging modalities like fluorescence imaging and magnetic resonance imaging (MRI). They can also be used in biosensors for disease diagnosis and monitoring. CeO2 nanoparticles offer several advantages for biomedical applications such as the following: (i) Biocompatibility: CeO2 nanoparticles have demonstrated good biocompatibility, making them suitable for in vivo applications. However, thorough biocompatibility evaluations are necessary for each specific application. (ii) Tailorable properties: The properties of CeO2 nanoparticles can be customized by controlling their size, surface modification, and functionalization, enabling their optimization for specific biomedical functions. (iii) Potential therapeutic benefits: The antioxidant and cytoprotective effects of CeO2 nanoparticles hold promise for treating various diseases associated with oxidative stress (Eom  & Choi, 2009). However, challenges that need to be addressed likewise. (iv) Long-term safety: The long-term effects and potential toxicity of CeO2 nanoparticles in the human body require further investigation to ensure their safe use. (v) Regulatory considerations: Regulatory frameworks need to be established to govern the use of CeO2 nanoparticles in biomedical applications, ensuring their safe and effective implementation.

Cerium Oxide Nanoparticles for Biomedical Applications

177

CeO2 nanoparticles present significant potential for a wide range of biomedical applications, including antioxidant therapies, drug delivery, tissue engineering, and imaging. Their unique properties and customizable characteristics make them a versatile nanomaterial in the biomedical field. As research continues, addressing the challenges and ensuring their safety and efficacy will pave the way for successfully translating CeO2 nanoparticles into practical biomedical solutions, contributing to improved diagnostics, therapies, and regenerative medicine.

Introduction Cerium oxide nanoparticles are a type of nanoparticles made from rare earth metals, and they have a unique structure called fluorite (Lord et al., 2021; Inbaraj & Chen, 2020). These nanoparticles can undergo a reversible conversion between Ce3+ and Ce4+ on their surface, giving them excellent redox properties and the ability to self-­ regenerate. Due to their special nanostructure and electronic properties, cerium oxide nanoparticles find applications in various fields like biosensors (Gao et al., 2019) and combustion aids (Cassee et al., 2011). Recent studies have shown that cerium oxide nanoparticles can imitate the functions of different enzymes, such as oxidase (Baldim et al., 2020; Cheng et al., 2016), catalase (Pirmohamed et al., 2010), peroxidase, superoxide dismutase (Kalashnikova et al., 2020), and even phosphatase (Liu & Liu, 2020). This versatility allows them to be used therapeutically for various diseases related to oxidative stress, such as chronic inflammation (Hirst et al., 2009), diabetes (Khurana et al., 2018; Hosseini et al., 2013; Chai & Tang, 2021), neurological disorders (Cimini et al., 2012; Kwon et al., 2016), lung injury (Xu et al., 2016), liver disease (Casals et al., 2021; Cheng et al., 2013), cardiac hypertrophy (Jain et al., 2021), and cancer (Alili et al., 2012). It is widely known that producing metal particles at the nanoscale size can significantly enhance their ability to fight against cancer and harmful microbes. To achieve this, it is crucial to use an effective technique that allows precise control over the size of these nano-sized metal particles during their preparation (Wang et al., 2022). Like other rare earth metal oxides, nanoparticles have numerous applications in energy, information technology, medical sciences, and environmental protection. Their unique properties are mainly determined by their size, elemental composition, and self-organized structures, making them valuable as antimicrobial agents and in various technological fields. Among these rare earth metal oxides, Er2O3, CeO2 NPs, and CeO2/Er2O3 nanocomposites have particularly caught the attention of researchers in material science and technology due to their remarkable properties and potential applications (Balaraman et al., 2023). Minute cerium oxide particles (less than 5 nm) have been found to be more enzymatically active because they possess a larger specific surface area (Tong et  al., 2020; Siposova et al., 2022). However, when these particles are in biological fluids, they have a tendency to clump together, reducing their specific surface area and, consequently, enhancing their enzymatic activity (Baldim et al., 2020). Nano-sized

178

A. Vijayan et al.

cerium oxide possesses several attractive properties, including a low energy band gap, high oxygen storage capacity, and excellent oxygen mobility. In addition, nano-structured materials containing Er3+ ions are of great interest because they exhibit unique optical and electrical properties that depend on the particle size at the nanoscale (Balaraman et al., 2023). These features make it a valuable material for various industrial applications, such as in polishing agents, sunscreens, fuel cells, optoelectronics, photocatalysts, solid-state electrolyte sensors, and applications related to electrical, optical, photoluminescence, and biomedicine (Jasinski et al., 2003; Xu et al., 2016; Janoš et al., 2016; Hemalatha & Rukmani, 2016; Skirtach et al., 2006). The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has sparked significant research efforts to understand and combat the virus. The virus is highly infectious, leading to the human coronavirus disease 2019 (COVID-19) disease in humans. This has driven scientists to study the virus’s structure and mechanisms causing the disease (Walls et  al., 2020, 2019; Baker et  al., 2020). Respiratory viruses, like SARS-CoV-2, pose a continuous threat to human populations due to their high transmissibility and infectivity. Novel variants of these viruses emerge regularly as they spread among people. Targeting these viruses with pharmaceutical interventions is challenging due to their specific interactions. For instance, the spike protein of coronaviruses has a protective glycan shield that prevents nonspecific binding (Grant et al., 2020; Casalino et al., 2020; Watanabe et al., 2020). Moreover, the increasing problem of antibiotic and antimicrobial drug resistance makes the development of small-molecule therapeutics difficult (Theuretzbacher, 2013; Levy & Marshall, 2004). Additionally, with numerous variants emerging, finding high-specificity inhibitors becomes problematic. Scientists have extensively investigated the use of metal and metal oxide nanomaterials in various antibacterial and antiviral applications, particularly for combating harmful pathogens. Nanomaterials based on transition metals have shown remarkable effectiveness against a wide range of bacteria and viruses (Xiang et al., 2011; Galdiero et al., 2011; Gaikwad et al., 2013). Moreover, these materials exhibit greater resistance to deactivation under different physical and chemical conditions when compared to conventional small-molecule drugs or biological agents. Silver and cerium, in particular, have been widely used in medical and personal care products due to their strong antimicrobial properties (Prabakaran & Mani, 2019). However, despite their widespread application, the use of these nanomaterials are still limited by their stability in specific targeted applications (Neal et al., 2021). This book chapter offers valuable perspectives on the utilization of CeO2 NPs across multiple domains. These include their role as bactericidal and virucidal agents, elucidating their mechanisms of action. The chapter also delves into the advantages and disadvantages of CeO2 NPs, highlighting their potential benefits and limitations. Furthermore, it provides an overview of the recent progress and developments in this area of research, showcasing the advancements made thus far. Lastly, the chapter offers insightful future perspectives, presenting potential directions for further exploration and application of CeO2 NPs.

Cerium Oxide Nanoparticles for Biomedical Applications

179

Table 1  Brief examples of advantages of CeO2 NPs Advantages Potent antioxidant properties Enhanced catalytic activity Biocompatibility Potential for drug delivery systems Versatile applications in nanotechnology

Disadvantages Potential toxicity and safety concerns Environmental impact Agglomeration and dispersion issues Cost of production Limited stability in certain conditions

Fig. 1  Schematic diagram of the biomedical applications of cerium oxide nanoparticles. (Adapted from Yadav et al., 2023)

Advantages and Disadvantages The key advantages and disadvantages are given briefly in Table 1. The overview of biomedical applications of CeO2 NPs is given in Fig.  1 (adapted from Yadav et al., 2023).

180

A. Vijayan et al.

Antimicrobial Activity of Green-Mediated CeO2 NPs The enchanting antibiotics have proven to be ineffective on the clinical side. As a result, there is an increasing need to discover alternatives to traditional antibacterial agents to address drug-resistant bacteria. Nanomaterials have gained significant attention over the last few decades due to their unique physiochemical properties arising from their reduced size. This heightened interest spans not only across industries but also within the field of biomedicine. Nanoparticles (NPs), in conjunction with polymers, liposomes, micelles, and dendrimers, have found applications in treating numerous diseases and infections (Zhang et al., 2019; Shrivastava et al., 2007; Sondi & Salopek-Sondi, 2004; Stoimenov et al., 2002). In recent times, there has been a notable surge of interest in CeO2 NPs as antimicrobial agents, owing to their relatively minimal or even nonexistent toxicity toward mammalian cells, especially in comparison to silver and copper counterparts. Notably, Chen et al. (2014) highlighted that CeO2 NPs and Au/CeO2 NPs showed no toxicity to RAW 264.7 normal cells, even at doses between 1 and 1000 μmol L−1. Conversely, these nanoparticles exhibited substantial cytotoxicity toward A549 cancer cells. Furthermore, CeO2 NPs exhibit remarkable longevity, maintaining high efficiency over extended periods. Unlike other nanoparticles (such as ZnO NPs and TiO2 NPs), CeO2 NPs possess a distinct antibacterial mechanism rooted in their characteristic mixed valence states. This mechanism involves a reversible conversion cycle (Ce4+  →  Ce3+  →  Ce4+) that autonomously persists on the nanoparticle surface (Khashan et al., 2021). Unlike TiO2 NPs that require UV light to function, CeO2 NPs manifest antibacterial effects without external triggering. Given the substantial abundance of cerium on earth, the potential of CeO2 NPs as promising materials beckons further investigation (Zhang et al., 2019; Pagnout et al., 2021; Wasa et al., 2022). Effectively addressing bacterial diseases requires a proactive search for innovative antibacterial agents. The utilization of antibacterial nanomedicines stands as a strategic approach in the ongoing battle against antibiotic resistance. In a prior investigation, the antimicrobial efficacy of CeO2 NPs were assessed in two distinct sizes (CeO2 NP1 [1–2 nm] and CeO2 NP2 [10–12 nm]), while also assessing their impact on eukaryotic cells’ cytotoxicity. The study involved analyzing antimicrobial activity, the impact on DNA cleavage, microbial cell viability, and inhibition of biofilm formation (Amaro et al., 2021). Furthermore, the influence of CeO2 NPs on erythrocyte eryptosis was evaluated through annexin V staining and flow cytometry. Both CeO2 NP1 and CeO2 NP2 were capable of cleaving single-strand DNA. These nanoparticles exhibited complete inhibition of microbial cell viability at a 500 mg/L concentration. Additionally, CeO2 NP1 and CeO2 NP2 effectively hindered biofilm formation in S. aureus and P. aeruginosa, with larger CeO2 NPs demonstrating reduced toxicity toward erythrocytes compared to their smaller counterparts. The CeO2 NPs possess moderate antimicrobial activity and limited cytotoxicity on erythrocytes, positioning them as promising candidates for antibacterial applications (Stabryla et al., 2021; Yefimova et al., 2022; Muduli et al., 2023). Cerium stands out among the 17 rare earth elements due to its exceptionally high natural abundance (approximately 66.5 ppm), surpassing that of copper (60 ppm)

Cerium Oxide Nanoparticles for Biomedical Applications

181

and tin (2.3 ppm). Beyond its use as an essential engineering material, CeO2 finds diverse applications, such as catalysts or catalyst supports, polishing agents, fuel cell electrolytes, superconductor buffer layers, oxygen storage materials, and ultraviolet–visible (UV) absorbents. The biomedical sector has recently noticed the antioxidant capability of CeO2, as it showcases the potential to safeguard cells against radiation-induced damage, oxidative stress, and inflammation (Celesti et al., 2022). Notably, Hirst et  al. (2009) demonstrated that CeO2 NPs can mitigate oxidative stress and suppress the expression of the proinflammatory i-NOS protein in J774A.1 murine macrophages. The study observed that CeO2 NPs with ample vacancies offered nearly 99% protection to normal cells from radiation. In contrast, minimal protection was witnessed for tumor cells at equivalent CeO2 NPs concentrations. Although there are limited reports on the impact of CeO2 NPs on mammalian cells, their antibacterial effects have received comparatively less attention. Remarkably, CeO2 also exhibits pro-oxidative behavior beyond its antioxidative property, enabling it to induce oxidative stress and thereby exhibit toxicity toward cancer or bacterial cells. The characteristics of a substance are shaped by its underlying structure. Thus, attaining a comprehensive understanding of the intricacies of CeO2’s structure would provide valuable insights into its antibacterial mechanism and could potentially facilitate the prediction of antibacterial behavior in novel CeO2-based nanoparticles. CeO2 adopts a face-centered cubic (FCC) fluorite crystal structure, wherein Ce4+ occupies octahedral interstitial sites and O2− occupies tetrahedral interstitial sites. Among CeO2’s pivotal attributes, the reversible transformation between Ce(III) and Ce(IV) (antioxidant/pro-oxidant) stands out, closely tied to the generation and migration of oxygen vacancies. These oxygen vacancies, abundant in CeO2 NPs, contribute to an impressive oxygen storage capacity (OSC), a foundational trait that underpins various applications of CeO2 NPs, notably in catalysis. At the subcellular level, nanomaterials exert their cytotoxic effects, with NPs presenting expanded opportunities for biomolecular interactions. Upon adsorption of CeO2 NPs onto bacterial membrane surfaces, they might associate with mesosomes, disrupting cellular respiration, DNA replication, and cell division, while also augmenting bacterial membrane surface area. Relevant studies have suggested that ions released from nanomaterials might interact with thiol groups (–SH) found in proteins located on bacterial membranes. These proteins go beyond the cell membrane and function as pathways for nutrient transport. This interaction between nanomaterials and proteins leads to decreased membrane permeability and eventual cell deterioration. (Zhang et al., 2019; Joshi et al., 2020; Khashan et al., 2021; Kamat & Kumari, 2023) (Fig. 2). Nanoparticles (NPs) have exhibited significant potential in antimicrobial applications, yielding noteworthy outcomes (Nadeem et al., 2017, 2018; Murray et al., 2022). Specifically, the antimicrobial efficacy of CeO2 NPs has garnered significant attention, particularly in combating bacterial pathogens (Kumar et  al., 2018; Sebastiammal et al., 2019; Kamat et al., 2022). Although the precise mechanism for microbial eradication remains elusive, it is postulated that CeO2 NPs predominantly induce microbial death through the extensive generation of ROS within cells, as illustrated in Fig. 3. The ability of CeO2 NPs to kill bacteria is attributed to their potent electrostatic properties, distinctive morphologies, small size, and low band energy. By virtue of

182

A. Vijayan et al.

Fig. 2  Diagrammatic representation of toxicity of CeO2 NPs against bacterial pathogens. (Adapted from Zhang et al., 2019)

their robust electrostatic potential, CeO2 NPs interact with thiol groups within membrane proteins, resulting in protein denaturation and membrane impermeability, ultimately leading to microbial demise (Kunga Sugumaran et al., 2016). Exposure to CeO2 NPs initiates microbial death via membrane disruption through mesosome attachment, impairment of cellular compartments, and perturbation of bioorganic molecules, culminating in disrupted metabolism and physiology. Similarly, green-­ synthesized NPs employ a comparable approach to eliminate pathogens, utilizing various biological species (McNeilly et al., 2021; Yonathan et al., 2022). A novel therapeutic avenue, biogenic CeO2 NPs, has exhibited promising outcomes in tackling multidrug-resistant bacteria, suggesting potential against refractory pathogenic strains (Maqbool et al., 2018). CeO2 NPs, in conjunction with other compounds, have been integrated into diverse organic and inorganic hybrids to enhance antimicrobial responses. Similarly, bio-mediated CeO2 NPs disrupt fungi by the generation of numerous free radicals and ROS, leading to distorted structure and physiological dysfunction, ultimately resulting in fungal death. However, our understanding of fungi in this context remains limited. Despite advancing knowledge regarding the antimicrobial attributes of CeO2 NPs, many aspects, such as their precise antibacterial mechanism, toxicity profile, in vivo assessments, and environmental implications, remain shrouded in uncertainty and warrant further exploration. Furthermore, leveraging the low band energy potential of CeO2 NPs could enable the creation of sterile surfaces in hospital and laboratory settings, potentially

Cerium Oxide Nanoparticles for Biomedical Applications

183

Fig. 3  Schematic representation of antibacterial activity of CeO2 nanoparticles. (1) Cell wall disruption, (2) cell membrane disintegration, (3) free radicals productions, (4) loss of protein peptides, (5) DNA fragmentation, (6) vital enzymes inhibition, (7) loss of cellular fluids, and (8) disruption in electron transport. (Adopted from Nadeem et al., 2020)

reducing nosocomial and other acquired infections (Nadeem et al., 2020; Armijo et al., 2020; Joudeh & Linke, 2022). Apart from their uses in fighting against microbes, CeO2 NPs have found utility in addressing various other medical conditions. Notably, biogenic CeO2 NPs have emerged as a promising avenue for treating diverse cancers, including osteosarcoma, colon, cervical, and breast cancers. Research findings have highlighted the potent anticancer capabilities of these nanoparticles, making them potential candidates for chemotherapeutic applications due to their low toxicity and ability to trigger apoptosis or necrosis in cancerous cells (Armijo et al., 2020). Despite the impressive pharmacological prospects of biogenic CeO2 NPs, several crucial factors require elucidation. These include understanding the mechanism of

184

A. Vijayan et al.

action, determining the optimal minimum inhibitory concentration, and identifying the most effective delivery system. Furthermore, it is essential to thoroughly evaluate cytotoxicity and genotoxicity using in vivo models to ensure compatibility in both laboratory and real-life settings (Nadeem et  al., 2020; Nayem et  al., 2020; Bruna et al., 2021; Singh et al., 2021; Alghamdi, 2023).

Potent Antioxidant Properties Oxidative stress, which is the underlying cause of many serious diseases, arises from an imbalance between the body’s natural defenses against harmful free radicals and the generation of ROS within cells. CeO2 NPs have demonstrated their protective abilities in both laboratory (cell) and animal studies by reducing ROS levels. In the cellular environment, the superoxide radical anion (O2∙−) serves as a signaling molecule and is produced during normal cellular processes. However, excessive O2∙− levels can quickly increase during inflammation or when there are disruptions in the mitochondria’s electron transport chain, affecting adenosine triphosphate (ATP) production (Nelson et al., 2016). The body usually manages and reduces the harmful effects of excess O2∙− through the action of superoxide dismutase (SOD) enzymes present in the extracellular space, cytoplasm, and mitochondria (Mccord & Fridovic, 1969).

Anti-inflammatory Effects Sabeena et  al. (2023) evaluated CeO2 NPs’ anti-inflammatory properties and a super-nanocomposite using the bovine serum albumin (BSA) denaturation assay. They tested different concentrations of these NPs (ranging from 10 to 50 μL/mL) in the experiment. The results showed that all three NPs exhibited anti-inflammatory effects in a dose-dependent manner. Specifically, the proportion of anti-­inflammatory activity CeO2 NPs and the super-nanocomposite was 46.2%, and 74.8%, respectively. In line with this, a prior investigation discovered that the BSA denaturation method increased the anti-inflammatory effectiveness of CuO nanoparticles (Gnanasundaram & Balakrishnan, 2017; Sabeena et al., 2022a, b). Their findings are consistent with previous studies that observed anti-­ inflammatory effects in metal oxide nanoparticles like CuO nanoparticles. Furthermore, the super-nanocomposite and CeO2 NPs demonstrated anti-inflammatory activity with corresponding half-maximal inhibitory concentration (IC50) values (a measure of effectiveness) (Sabeena et  al., 2022a, b). The researchers concluded that the super-nanocomposite, specifically the CeO-SiO2 nanomaterials, shows promise as a potential candidate for developing powerful anti-­inflammatory drugs. Previous studies have also shown that different nanostructures can enhance the ability of proteins (like egg albumin) to resist denaturation, further supporting the potential of nanocomposites in anti-inflammatory applications (Anoop & Bindu, 2015; Govindappa et al., 2011).

Cerium Oxide Nanoparticles for Biomedical Applications

185

Biological Interaction  CeO2 NPs can interact with biological systems, including cells and tissues. The size, shape, surface charge, and coating of nanoparticles can influence their interaction with biological entities. These interactions could lead to various cellular responses, potentially affecting cell viability, oxidative stress, inflammation, and other physiological processes. Oxidative Stress  CeO2 NPs are known to exhibit both antioxidant and pro-oxidant properties. While their antioxidant behavior is of interest for applications in scavenging ROS, their pro-oxidant behavior could potentially lead to oxidative stress within cells and tissues. Oxidative stress is linked to various health issues, including cell damage, DNA damage, and even carcinogenesis (Matussin et al., 2022). Inflammation and Immune Response  Nanoparticles can trigger immune responses and inflammation in the body. The uptake of CeO2 NPs by immune cells could lead to immune system activation, which might be beneficial in some cases but could also cause chronic inflammation if not properly regulated. Accumulation and Distribution  The accumulation and distribution of nanoparticles in different organs and tissues are of concern. CeO2 NPs could potentially accumulate in organs such as the liver, spleen, and lungs. Prolonged accumulation in specific organs might lead to adverse effects over time. Environmental Impact  The potential release of CeO2 NPs into the environment could impact ecosystems. Understanding their behavior in soil and water systems and their potential to bioaccumulate in aquatic organisms are essential for assessing their environmental safety. Exposure Routes  People can be exposed to CeO2 NPs through various routes, including inhalation, ingestion, and dermal contact. Occupational exposure during manufacturing or research and consumer exposure through products containing CeO2 NPs are important considerations. Regulation and Risk Assessment  Regulatory agencies in different countries are working to establish guidelines and safety standards for nanoparticles, including CeO2 NPs. However, the rapidly evolving field of nanotechnology presents challenges in risk assessment and regulation. Mitigation Strategies  To address potential toxicity concerns, researchers are exploring various strategies, such as modifying nanoparticle properties (size, coating, surface charge), using proper handling protocols, and developing appropriate protective measures.

Toxicity of Nanomaterials When these nanoparticles interact with the cell culture medium, they irreversibly aggregate, making them much more toxic to cells (Ju et al., 2020). Researchers have observed that nanoparticles lacking targeted modifications are not taken up

186

A. Vijayan et al.

efficiently by cells, significantly limiting their availability for use in living organisms (Guo et al., 2020). Upon being exposed, nanoparticles belonging to three distinct categories—natural, incidental, and engineered—can interact with organs, tissues, cells, and biomolecules (Fig. 4). This interaction can lead to unfavorable and potentially harmful nano-bio-interactions, initiating subsequent mechanisms that may yield adverse effects and nanotoxicity. The emergence of nanoparticle toxicity is contingent upon several factors, including the manner of exposure, the quantity or dose administered, concentration, duration, and frequency. Conventionally, these fundamental facets of toxicity assessment are pertinent to evaluating the impacts of small-molecule drugs and various

Fig. 4  Schematic representation of nanoparticle adverse effects and nanotoxicity: (a) exposure pathways—nanoparticles can enter the body through various exposure pathways. (b) Interaction with organs/tissues—when exposed to nanoparticles, organs and tissues may experience interactions. (c) Cellular interactions—nanoparticles can interact with individual cells within the body. (d) Biomolecule interaction—nanoparticles can also interact with biomolecules present in the body. (e, i) ROS generation—one significant mechanism of nanoparticle toxicity is the creation of ROS, which can damage cells. (e, ii) Disintegration and release—nanoparticles might disintegrate, releasing metal ions and organic compounds that can contribute to toxicity. (e, iii) Cell signaling activation—nanoparticles can trigger cell signaling pathways, leading to cellular responses that contribute to toxicity. (f) Cellular effects—apoptosis and necrosis—nanoparticle-induced adverse effects can include cell death through apoptosis or necrosis. (g) Tissue/organ damage and inflammation—nanoparticle toxicity can result in tissue and organ damage, as well as the initiation of inflammatory responses and anaphylactic shock. (Adapted from Yang et al., 2021)

Cerium Oxide Nanoparticles for Biomedical Applications

187

compounds. In the realm of nanotoxicology, these criteria are equally applicable. However, in addition to these customary parameters, other pivotal elements influencing nanoparticle toxicity necessitate consideration. These encompass the physicochemical attributes of nanoparticles, such as their composition, dimensions, surface characteristics, and morphology. In contrast to small molecules, these supplementary physicochemical variables confer complexity upon the assessment of nanotoxicity, potentially requiring a tailored approach to evaluating nanoparticle-­induced toxicity for each case. For instance, even when the core nanomaterial remains constant, minor deviations in nanoparticle surface chemistry can yield substantial disparities in terms of toxicity, distribution throughout the body, and the elimination trajectory (Yang et al., 2021; Muhr et al., 2014; Elci et al., 2016; Poon et al., 2019).

Recent Applications of Cerium Nanoparticles In the world of science, researchers are buzzing with excitement about cerium nanoparticles and their potential. Here are some of the latest studies and findings: Fighting Bacteria  Scientists are investigating how cerium nanoparticles can help in the fight against harmful bacteria. These tiny particles have shown promise in preventing infections and keeping surfaces clean. Healing Properties  Researchers are exploring how cerium nanoparticles might aid in the healing process. These nanoparticles seem to have qualities that could help cells recover faster after injuries or surgeries. Reducing Pollution: There is a lot of interest in using cerium nanoparticles to make our environment cleaner. They might be used to break down harmful chemicals in water and air, making them safer for us and the planet. Better Drug Delivery: Scientists are studying how cerium nanoparticles could improve the delivery of medicines in our bodies. These nanoparticles might help get medications to the right places more effectively. Advanced Imaging: Cerium nanoparticles are also catching the eye of researchers working on advanced imaging techniques. These particles could make medical scans clearer and more detailed, helping doctors see inside our bodies better. Green Energy  Some researchers are looking into using cerium nanoparticles in renewable energy technologies. These particles could potentially boost the efficiency of solar cells, making green energy even more powerful. Protecting Against Radiation: There is an ongoing research into how cerium nanoparticles might shield our bodies from the harmful effects of radiation. This could have applications in medical treatments and even space exploration. Supporting Plant Growth  Farmers and scientists are curious about how cerium nanoparticles could improve crop growth. These nanoparticles might help plants grow stronger and withstand challenges like droughts. Safer Materials: In industries like construction and electronics, researchers are exploring how cerium nanoparticles could make materials safer and more durable. This could lead to longer-­lasting products and safer workplaces.

188

A. Vijayan et al.

Unlocking New Reactions  Some scientists are excited about how cerium nanoparticles could catalyze chemical reactions. This means they could help create new materials and processes that were previously difficult to achieve. Overall, researchers are uncovering exciting possibilities for cerium nanoparticles across a wide range of areas, from medicine and the environment to technology and beyond. As science continues to progress, we can expect even more groundbreaking discoveries involving these tiny yet mighty particles (Hamidian et al., 2021).

Biosensors for Biomedical Applications (Fig. 5) Nanozymes refer to nanomaterials that exhibit enzyme-like activities, mimicking the functions of natural enzymes (Huang et al., 2019; Lee et al., 2022). These nanozymes have garnered attention due to their notable attributes, including strong stability, customizable catalytic abilities, ease of modifying their surfaces, and the ability to be produced in large quantities. This has positioned them as a promising alternative to naturally occurring enzymes (Tang et al., 2021; Wang et al., 2023). Particularly intriguing is the surface of CeO2 NPs, which bears a mix of oxidation states (Ce3+ and Ce4+). This distinctive composition equips CeO2 NPs with a

Fig. 5  A graphic representation is presented, depicting how optical biosensors, built upon the exceptional physical and chemical attributes of CeO2 NPs, operate. These attributes encompass a range of enzyme-like activities, rapid electron transfer capacity, and a strong affinity for biomolecules with effective sensing mechanisms. (Adapted from Wang et al., 2023).

Cerium Oxide Nanoparticles for Biomedical Applications

189

wealth of oxygen vacancies and a high oxygen diffusion coefficient. These characteristics create favorable conditions for catalytic reactions and facilitate the conversion between Ce3+ and Ce4+ states (Jiang et al., 2019; Wu et al., 2019). As a result, CeO2 NPs exhibit a diverse range of enzyme-like catalytic activities. These include superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and phosphatase activities, showcasing their potential to function as mimics of various enzymes. This multifaceted enzymatic capability makes CeO2 NPs highly promising for integration into optical biosensors designed for in vivo biomedical applications (Wei & Wang, 2013; Charbgoo et al., 2017; Wang et al., 2023).

Dental Applications (Fig. 6) Nanoparticles find their way into dental materials like fillings, sealants, adhesives, and dentures to enhance these products’ qualities. Among the many types of nanoparticles made from metal oxides, CeO2 NPs stand out. They are recognized for their lower harm to cells in mammals and their special ability to combat bacteria. Moreover, they bring a host of powerful traits to the table, including fighting tumors, reducing inflammation, battling bacteria, and even acting as a sensor for the immune system (Jairam et al., 2023).

Fig. 6  Schematic diagram of different types of synthesis of CeO2 NPs and its role in biomedical and dental applications. (Adapted from Jairam et al., 2023)

190

A. Vijayan et al.

Antiviral Activity (COVID-19) One exciting application being explored for cerium nanoparticles (CeNPs) are their potential in viral disease therapy. Researchers have been actively investigating the antiviral properties of CeNPs, ever since their antiviral activity was first discovered by Zholobak et  al. (2010). These nanoparticles have demonstrated the ability to combat viruses effectively. CeNPs have exhibited remarkable antiviral and virucidal properties in a range of studies (Fig. 7). They have shown the capacity to protect against viruses like Indiana vesicular stomatitis virus (VSV) in various cell lines, including mouse fibroblasts (L929), embryonic piglet testicles (EPT), and swine testicular (ST) cells (Zholobak et al., 2010, Shydlovska et al., 2018). Additionally, CeNPs have displayed their effectiveness against herpes simplex virus 1 (HSV-1) in normal rat fibroblast (FR) cell lines (Shydlovska et al., 2018). Excitingly, CeNPs functionalized with interferon have been identified as a potential antiviral agent for treating systemic herpetic infections (Shydlovska et al., 2018, Zholobak et al., 2014). Recent research has extended the scope of CeNPs’ antiviral potential, with investigations into their activity against Sabin-like poliovirus (Mohamed et al., 2020). Moreover, the utilization of CeNPs against the SARS-CoV-2 coronavirus, responsible for COVID-19, has been considered (Allawadhi et  al., 2020). CeNPs have

Fig. 7  Schematic illustration of a possible mechanism of CeNPs’ effect on virus invasion. (Adopted from Dupkalova et al., 2023)

Cerium Oxide Nanoparticles for Biomedical Applications

191

exhibited virucidal activity against a range of viruses, including SARS-CoV-2, transmissible gastroenteritis virus (TGEV), encephalomyocarditis virus (EMCV), and influenza virus (A/WSN/1933), across various cell lines. Additionally, CeNPs have demonstrated antiviral properties against bacteriophages enveloped phi6 (DSM21518) and non-enveloped MS2 (DSM21428) in their respective host bacteria, Pseudomonas sp. (DSM21428) and Escherichia coli (DSM5695). Beyond their direct antiviral effects, CeNPs have exhibited the potential to enhance the immunogenicity of influenza vaccines (Zholobak et  al., 2016). Moreover, they have shown promise as effective carriers and adjuvants in antiviral therapies (Shcherbakov et al., 2020). Recent research by Nefedova et  al. (2022) has unveiled the enhanced virucidal activity of CeNPs against enveloped viruses, while their impact on non-enveloped viruses was comparatively lower. This enhanced virucidal activity could potentially be attributed to their interference with the fusion between viral and host cell membranes (Shcherbakov et al., 2014; Nefedova et al., 2022). This interaction holds significance at the point of endocytosis, where CeNPs and viruses converge in endosomes. The acidic conditions of endosomes facilitate this interaction, where histidine residues in the viral proteins play a crucial role. These interactions disrupt the structural changes essential for viral fusion, suggesting a potential avenue for designing antiviral agents (Kampmann et al., 2006, Da Poian et al., 2009). In essence, the research landscape is uncovering a promising role for CeNPs in viral therapy, particularly through their interference with viral fusion mechanisms. This knowledge not only enhances our understanding of antiviral strategies but also opens up avenues for the development of innovative antiviral treatments (Nefedova et al., 2022). The use of CeO2 has attracted attention in the fight against COVID-19 due to its unique characteristics, including its high oxygen storage capacity and redox activity  (Rocha et al., 2022). It is believed that these properties could be utilized to reduce oxidative stress and inflammation related to COVID-19, and also enhance the immune response against the virus. Additionally, cerium dioxide nanoparticles have shown potential in blocking the entry of the virus into host cells and inhibiting viral replication. However, more research is needed to fully understand the mechanisms underlying these effects and to develop effective therapeutic interventions. Recently, researchers have investigated the use of CeO2@NH2-­functionalized electrodes for the rapid detection of the binding receptor domain of the SARS-CoV-2 spike protein (Triastuti et al., 2003). CeO2 is a material that has demonstrated exceptional properties in various fields, such as catalysis, electrochemistry, and biomedicine. In this context, it has been employed to potentially increase the sensitivity and selectivity in detecting biomolecules, particularly the receptor binding domain of the SARSCoV-2 spike protein. In another study, the researcher describes an enzyme-linked immunosorbent assay using Au@CeO2@Pt enzymes for colourimetric and fluorescent detection of the SARS-CoV-2 nucleocapsid protein (Aoqing et al., 2023). Nanozymes are nanomaterials with enzyme-like activity used to develop sensitive and specific detection methods. This approach could have significant applications in early and rapid detection of the SARS-CoV-2 virus. The CeO2 nanoparticles in this study likely enhance the catalytic activity of the nanozyme, contributing to its peroxidase-like function. This enhancement could play a crucial role in the colorimetric and fluorescent detection of the SARS-CoV-2 nucleocapsid protein, potentially improving the

192

A. Vijayan et al.

sensitivity and specificity of the assay. Overall, CeO2 nanoparticles have been studied for their potential role in mitigating inflammation and oxidative stress, which are relevant factors in COVID-19 pathogenesis.

Conclusion and Future Perspectives In the rapidly evolving biomedical research landscape, CeO2 NPs have emerged as dynamic players with versatile potential. Their unique catalytic and redox properties position them at the forefront of innovative biomedical applications. This comprehensive overview has shed light on the dual nature of CeO2 NPs, highlighting their advantageous antioxidative behavior and potential pro-oxidant effects, necessitating a balanced assessment for their biomedical integration (Murali et al., 2019; Singh et al., 2021; Cam et al., 2022). The exploration of CeO2 NPs’ antimicrobial applications presents a promising avenue for revolutionizing infection control. Their prowess in mitigating bacterial growth, combating biofilm formation, and countering antibiotic-resistant strains holds immense potential for addressing the growing challenges of antimicrobial resistance. Moreover, in the context of the COVID-19 pandemic, the demonstrated antiviral capabilities of CeO2 NPs offer a glimmer of hope. Recent research indicates their effectiveness as inhibitors of viral enzymes and agents for surface sanitation, amplifying their significance in our ongoing battle against the pandemic. However, as the potential benefits of CeO2 NPs in biomedicine become clearer, the chapter also underscores the importance of understanding their toxicity implications. While their antioxidant properties hold promise for therapeutic interventions in oxidative stress-related diseases, concerns regarding oxidative stress and inflammation demand rigorous investigation. This dualistic nature of CeO2 NPs necessitates a thorough risk-benefit analysis to ensure their safe and effective incorporation into medical practices (CDC, 2019; Basak & Packirisamy, 2020; Weiss et al., 2020; Emam et al., 2023). Looking ahead, the realm of CeO2 NP research is prevalent with exciting possibilities. Ongoing studies continue to unveil novel facets of their behavior, interactions, and applications. These insights lay the foundation for innovative therapeutic strategies, personalized medical interventions, and enhanced disease management approaches. As the world of medicine increasingly embraces the potential of nanotechnology, CeO2 NPs stand poised to play a pivotal role in shaping the future of healthcare and medicine (Matussin et al., 2023). However, a central and often debated question regarding cerium nanoparticles revolves around their potential toxicity. However, due to the intricate nature of nanoparticle toxicity, arriving at a definitive answer is elusive. Prudence dictates that we approach the matter with caution and avoid making sweeping statements about the safety and toxicity of nanoparticles. Presently, assessing cerium nanoparticle toxicity mandates meticulous case-by-case examination, given that various factors, including nanoparticle properties, exposure pathways, dosage, and duration, collectively shape biological and pathological effects. This standpoint finds alignment with recent wellconsidered editorials, perspectives, and correspondences centered on the assessment

Cerium Oxide Nanoparticles for Biomedical Applications

193

of nanoparticle risks and safety (Yang et al., 2021; Muhr et al., 2014; Elci et al., 2016; Poon et al., 2019). Notably, nanotoxicity constitutes a notably vital and timely domain of research, given the inevitable escalation of human exposure to diverse nanoparticle classifications and types in the days to come (Nefedova et al., 2022). The standardization of nanoparticle dosage metrics within experimental designs and data representation stands as a critical factor that would foster efficient data analysis and the development of computational strategies, like the NanoSolveIT initiative (Afantitis et al., 2020; Yang et al., 2021). This project integrates physics-­ based and data-driven models, encompassing toxicogenomics and biokinetics, to create comprehensive in silico nanoparticle risk assessments (Afantitis et al., 2020). Beyond dosage metrics, consistency in experimental setup and data depiction will be pivotal across all aspects of nanoparticle toxicity testing, a necessity for training predictive computational models.

Future Perspectives The journey of CeO2 NPs in biomedicine holds promising horizons for continued exploration. Moving forward, several key directions warrant attention: 1. Tailored Therapeutic Strategies: As our understanding of CeO2 NPs’ pro-oxidant and antioxidant behaviors deepens, future research can focus on designing tailored therapeutic strategies. This entails optimizing their formulations to harness their benefits while mitigating potential risks. 2. Precision Medicine: With their potential to induce oxidative stress, CeO2 NPs could be harnessed in precision medicine approaches. Their selective impact on cells could be leveraged for targeted therapies, minimizing collateral damage to healthy tissues. 3. Multidisciplinary Collaboration: As demonstrated by their relevance in the fight against COVID-19, CeO2 NPs showcase the power of multidisciplinary collaboration. Collaborations between researchers, clinicians, engineers, and industry can unlock innovative solutions and accelerate translation into practical applications. 4. Safety Assessment Protocols: Future efforts must also focus on establishing standardized protocols for assessing the safety of CeO2 NPs. Rigorous and reproducible methodologies will be critical to ensure their clinical viability. 5. Clinical Translation: The rapid pace of CeO2 NPs research underscores the importance of parallel efforts in clinical translation. Rigorous preclinical studies and robust clinical trials are essential to validate their efficacy and safety in real-­ world scenarios. In conclusion, the journey of cerium oxide nanoparticles in biomedicine is dynamic and promising. Their unique properties, combined with diligent research and collaboration, have the potential to reshape healthcare paradigms and improve patient outcomes. By addressing challenges, embracing innovation, and fostering interdisciplinary cooperation, the future of CeO2 NPs in biomedicine holds the promise of more effective, personalized, and safer medical interventions.

194

A. Vijayan et al.

Acknowledgement Author AV acknowledges the authorities of SRM Institute of Science and Technology, SRM University, Tiruchirappalli, for providing facilities. Authors RS, and MG greatly acknowledge the management of Bishop Heber College (Autonomous), Tiruchirappalli, for providing the necessary support to complete it successfully. Author NS thankful to the support of Chiang Mai University, Thailand.  Author KVP is thankful to the support Fondecyt 1211118, ANID, and Facultad de Ingeniería, Arquitectura y Deseno, Universidad San Sebastian, Lientur 1457, Concepcion, 4080871, Chile, for providing support. Conflict of interest  There is no conflict of interest.

References Afantitis, A., Melagraki, G., Isigonis, P., Tsoumanis, A., & Varsou, D. D. (2020). NanoSolveIT Project: Driving nanoinformatics research to develop innovative and integrated tools for in silico nanosafety assessment. Computational and Structural Biotechnology Journal, 18, 583–602. Alghamdi, A. A. A. (2023). Biogenic Mg doped CeO2 nanoparticles via Hibiscus sabdariffa and its potential biological applications. Journal of Umm Al-Qura University for Applied Sciences, 9, 132–141. Alili, L., Sack, M., Von Montfort, C., Giri, S., Das, S., Carroll, K.  S., Zanger, K., Seal, S., & Brenneisen, P. (2012). Downregulation of tumor growth and invasion by redox-active nanoparticles. Antioxidants & Redox Signaling, 19, 765–778. Allawadhi, P., Khurana, A., Allwadhi, S., Joshi, K., Packirisamy, G., & Bharani, K.  K. (2020). Nanoceria as a possible agent for the management of COVID-19. Nano Today, 35, 100982. https://doi.org/10.1016/j.nantod.2020.100982 Amaro, F., Moron, A., Díaz, S., Martín-González, A., & Gutiérrez, J.  C. (2021). Metallic nanoparticles-­friends or foes in the battle against antibiotic-resistant bacteria? Microorganisms, 9, 1–11. https://doi.org/10.3390/microorganisms9020364 Anoop, M.  V., & Bindu, A.  R. (2015). In-vitro anti-inflammatory activity studies on Syzygium zeylanicum (L) DC leaves. International Journal of Pharma Research & Review, 4(8), 18–27. Aoqing, C., Yue, S., Fubin, P., Xihui, M., Bin, D., Zhaoyang, T., Qingli, H. Mingzhu, X., Wu, L., & Bing, L. (2023). Nanozymelinked immunosorbent assay based on Au@CeO2@Pt nanozymes for colorimetric and fluorescent detection of SARS-CoV-2 nucleocapsid protein. Microchemical, 194, 109263. Armijo, L. M., Wawrzyniec, S. J., & Kopciuch, M. (2020). Antibacterial activity of iron oxide, iron nitride, and tobramycin conjugated nanoparticles against Pseudomonas aeruginosa biofilms. Journal of Nanbiotechnology, 18, 35. Baker, A. N., Richards, S.-J., Guy, C. S., Congdon, T. R., Hasan, M., Zwetsloot, A. J., Gallo, A., Lewandowski, J. R., Stansfeld, P. J., & Straube, A. (2020). The Sars-Cov-2 spike protein binds sialic acids and enables rapid detection in a lateral flow point of care diagnostic device. ACS Central Science, 6, 2046–2052. Balaraman, S., Iruson, B., Krishnmoorthy, S., Elayaperumal, M., & Sangaraju, S. (2023). Synthesis of Er2O3 blended CeO2 nanocomposites and investigation of their biomedical applications. Chemical Physics Impact, 6, 100167. Baldim, V., Yadav, N., Bia, N., Graillot, A., Loubat, C., Singh, S., Karakoti, A.  S., & Berret, J. F. (2020). Polymer-coated cerium oxide nanoparticles as oxidoreductase-like catalysts. ACS Applied Materials & Interfaces, 12, 42056–42066. Basak, S., & Packirisamy, G. (2020). Nano-based antiviral coatings to combat viral infections. Nano-Struct. Nano-Objects, 24, 100620. Bruna, T., Maldonado-Bravo, F., Jara, P., & Caro, N. (2021). Silver nanoparticles and their antibacterial applications. International Journal of Molecular Sciences, 22, 7202.

Cerium Oxide Nanoparticles for Biomedical Applications

195

Cam, T. S., Omarov, S. O., Chebanenko, M. I., Izotova, S. G., & Popkov, V. I. (2022). Recent progress in the synthesis of CeO2-based nanocatalysts towards efficient oxidation of CO. Journal of Science: Advanced Materials and Devices, 7(1), 100399. Casalino, L., Gaieb, Z., Dommer, A.  C., Harbison, A.  M., Fogarty, C.  A., Barros, E.  P., Taylor, B.  C., Fadda, E., & Amaro, R.  E. (2020). Shielding and beyond: The roles of glycans in SARS-CoV-2 spike protein. ACS Central Science, 6(10), 1722–1734. https://doi. org/10.1101/2020.06.11.146522 Casals, G., Perramón, M., Casals, E., Portolés, I., Fernández-Varo, G., Morales-Ruiz, M., Puntes, V., & Jiménez, W. (2021). Cerium oxide nanoparticles: A new therapeutic tool in liver diseases. Antioxidants, 10, 660–666. Cassee, F. R., van Balen, E. C., Singh, C., Green, D., Muijser, H., Weinstein, J., & Dreher, K. (2011). Exposure, health and ecological effects review of engineered nanoscale cerium and cerium oxide associated with its use as a fuel additive. Critical Reviews in Toxicology, 41, 213–229. CDC—Interim Infection Prevention and Control Recommendations for Healthcare Personnel during the Coronavirus Disease 2019 (COVID-19) Pandemic. Available online: https://www.cdc. gov/coronavirus/2019-­ncov/hcp/infection-­control-­recommendations.html. (Accessed on 25 august 2023) Celesti, C., Gervasi, T., Cicero, N., Giofre, S. V., Espro, C., Piperopoulos, E., Gabriele, B., Mancuso, R., LoVecchio, G., & Iannazzo, D. (2022). Titanium surface modification for implantable medical devices with anti-bacterial adhesion properties. Materials (Basel), 15, 3283. Chai, W. F., & Tang, K. S. (2021). Protective potential of cerium oxide nanoparticles in diabetes mellitus. Journal of Trace Elements in Medicine and Biology, 66, 126742. Charbgoo, F., Ramezani, M., & Darroudi, M. (2017). Bio-sensing applications of cerium oxide nanoparticles: Advantages and disadvantages. Biosensors and Bioelectronics, 96, 33–43. Chen, B. H., Suresh Babu, K., & Anandkumar, M. (2014). Cytotoxicity and antibacterial activity of gold-supported cerium oxide nanoparticles. International Journal of Nanomedicine, 9, 5515. Cheng, G., Guo, W., Han, L., Chen, E., Kong, L., Wang, L., Ai, W., Song, N., Li, H., & Chen, H. (2013). Cerium oxide nanoparticles induce cytotoxicity in human hepatoma SMMC-7721 cells via oxidative stress and the activation of MAPK signaling pathways. Toxicology In Vitro, 27, 1082–1088. Cheng, H., Lin, S., Muhammad, F., Lin, Y., & Wei, H. (2016). Rationally modulate the oxidase-like activity of nanoceria for self regulated bioassays. ACS Sensors, 1, 1336–1343. Cimini, A., D’Angelo, B., Das, S., Gentile, R., Benedetti, E., Singh, V., Monaco, A. M., Santucci, S., & Seal, S. (2012). Antibody-conjugated PEGylated cerium oxide nanoparticles for specific targeting of aggregates modulate neuronal survival pathways. Acta Biomaterialia, 8, 2056–2067. DaPoian, A. T., Carneiro, F. A., & Stauffer, F. (2009). Viral inactivation based on inhibition of membrane fusion: Understanding the role of histidine protonation to develop new viral vaccines. Protein and Peptide Letters, 16, 779. Dupkalov, D., Kosto, Y., Kalinovych, V., Deineko, A., Franchi, S., Novakova, J., Matolinov, I., Skala, T., Prince, K. C., Fucikova, A., Shcherbakov, A. B., Zholobak, N. M., & Tsud, N. (2023). Histidine- and glycine-functionalized cerium oxide nanoparticles: Physicochemical properties and antiviral activity. Applied Surface Science, 636, 157793. Elci, S. G., Jiang, Y., Yan, B., Kim, S. T., Saha, K., Moyano, D. F., Yesilbag Tonga, G., Jackson, L. C., Rotello, V. M., & Vachet, R. W. (2016). Surface charge controls the sub-organ biodistributions of gold nanoparticles. ACS Nano, 10(5), 5536–5542. Emam, M. H., Elezaby, R. S., Swidan, S. A., Loutfy, S.A., & Hathout, R. M. (2023). Cerium Oxide Nanoparticles/Polyacrylonitrile Nanofibers as Impervious Barrier against Viral Infections. Pharmaceutics, 15, 1494. https://doi.org/10.3390/pharmaceutics15051494. Eom, H.  J., & Choi, J. (2009). Oxidative stress of CeO2 nanoparticles via p38-Nrf-2 signaling pathway in human bronchial epithelial cell, Beas-2B. Toxicology letters, 187(2), 77–83. Gaikwad, S., Ingle, A., Gade, A., Rai, M., Falanga, A., Incoronato, N., Russo, L., Galdiero, S., & Galdiero, M. (2013). Antiviral activity of myco-synthesized silver nanoparticles against herpes simplex virus and human parainfluenza virus type 3. International Journal of Nanomedicine, 8, 4303.

196

A. Vijayan et al.

Galdiero, S., Falanga, A., Vitiello, M., Cantisani, M., Marra, V., & Galdiero, M. (2011). Silver nanoparticles as potential antiviral agents. Molecules, 16, 8894–8918. Gao, Z., Li, Y., Zhang, C., Zhang, S., Jia, Y., Li, F., Ding, H., Li, X., Chen, Z., & Wei, Q. (2019). AuCuxO- embedded mesoporous CeO2 nanocomposites as a signal probe for electrochemical sensitive detection of amyloid-beta protein. ACS Applied Materials & Interfaces, 11, 12335–12341. Gnanasundaram, I., & Balakrishnan, K. (2017). Synthesis and evaluation of anti-inflammatory activity of silver nanoparticles from Cissus vitiginea leaf extract. Journal of Nanoscience and Technology, 266–269. Govindappa, M., Naga, S. S., Poojashri, M. N., Sadananda, T. S., & Chandrappa, C. P. (2011). Antimicrobial, antioxidant and in vitro anti-inflammatory activity of ethanol extract and active phytochemical screening of Wedelia trilobata (L.) Hitchc. Journal of Pharmacognosy and Phytotherapy, 3(3), 43–51. Grant, O. C., Montgomery, D., Ito, K., & Woods, R. J. (2020). Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition. Scientific Reports, 10, 1–11. Guo, F., Fu, Q., Zhou, K., Jin, C., Wu, W., Ji, X., Yan, Q., Yang, Q., Wu, D., & Li, A. (2020). Matrix metalloprotein -triggered, cell penetrating peptide-modified star-shaped nanoparticles for tumor targeting and cancer therapy. Journal of Nanobiotechnology, 18, 48. Hamidian, K., Saberian. M. R., Miri, A., Sharifi, F., & Sarani, M. (2021). Doped and un-doped cerium oxide nanoparticles:Biosynthesis, characterization, and cytotoxic study. Ceramics International, 47(10):13895–13902. Hemalatha, K.  S., & Rukmani, K. (2016). Synthesis, characterization and optical properties of polyvinyl alcohol–cerium oxide nanocomposite films. RSC Advances, 6(78), 74354–74366. Hirst, S. M., Karakoti, A. S., & Tyler, R. D. (2009). Anti-inflammatory properties of cerium oxide nanoparticles. Small, 5, 2848–2856. Hosseini, A., Baeeri, M., Rahimifard, M., Navaei-Nigjeh, M., Mohammadirad, A., Pourkhalili, N., Hassani, S., Kamali, M., & Abdollahi, M. (2013). Antiapoptotic effects of cerium oxide and yttrium oxide nanoparticles in isolated rat pancreatic islets. Human & Experimental Toxicology, 32, 544–553. Huang, Y., Ren, J., & Qu, X. (2019). Nanozymes: Classification, catalytic mechanisms, activity regulation, and applications. Chemical Reviews, 119(6), 4357–4412. Inbaraj, B. S., & Chen, B. (2020). An overview on recent in vivo biological application of cerium oxide nanoparticles. Asian Journal of Pharmaceutical Sciences, 15, 558–575. Ioannou, M. E., Pouroutzidou, G. K., Chatzimentor, I., Tsamesidis, I., Florini, N., Tsiaoussis, I., Lymperaki, E., Komninou, P., & Kontonasaki, E. (2023). Synthesis and characterization of cerium oxide Nanoparticles: Effect of cerium precursor to gelatin ratio. Applied Sciences, 13, 2676. https://doi.org/10.3390/app13042676 Jain, A., Behera, M., Mahapatra, C., Sundaresan, N. R., & Chatterjee, K. (2021). Nanostructured polymer scaffold decorated with cerium oxide nanoparticles toward engineering an antioxidant and anti-hypertrophic cardiac patch. Materials Science and Engineering: C, 118, 111416. Jairam, L. S., Chandrashekar, A., Prabhu, T. N., Kotha, S. B., Girish, M. S., Devraj, I. M., Shri, M. D., & Prashantha, K. (2023). A review on biomedical and dental applications of cerium oxide nanoparticles―Unearthing the potential of this rare earth metal. Journal of Rare Earths. Janoš, P., Ederer, J., Pilařová, V., Henych, J., Tolasz, J., Milde, D., & Opletal T. (2016). Chemical mechanical glass polishing withcerium oxide: Effect of selected physico-chemical characteristics on polishing efficiency. Wear, 362, 114–120. Jasinski, P., Suzuki, T., & Anderson, H. U. (2003). Nanocrystalline undoped ceria oxygen sensor. Sensors and Actuators B: Chemical. 95(1–3), 73–77. Jiang, D., Ni, D., Rosenkrans, Z. T., Huang, P., Yan, X., & Cai, W. (2019). Nanozyme: New horizons for responsive biomedical applications. Chemical Society Reviews, 48(14), 3683–3704. Joshi, A. S., Singh, P., & Mijakovic, I. (2020). Interactions of gold and silver nanoparticles with bacterial biofilms: Molecular interactions behind inhibition and resistance. International Journal of Molecular Sciences, 21, 1–24. https://doi.org/10.3390/ijms21207658

Cerium Oxide Nanoparticles for Biomedical Applications

197

Joudeh, N., & Linke, D. (2022). Nanoparticle classification, physicochemical properties, characterization, and applications: A comprehensive review for biologists. Journal of Nanbiotechnology, 20, 262. Ju, X., Fucikova, A., Amid, B., Novakova, J., Matolinova, I., Matolin, V., Janata, M., Belinova, T., & Hubalek Kalbacova, M. (2020). Colloidal stability and catalytic activity of cerium oxide nanoparticles in cell culture media. RSC Advances, 10, 39373–39384. Kalashnikova, I., Chung, S., Nafiujjaman, M., Hill, M. L., Siziba, M. E., Contag, C. H., & Kim, T. (2020). Ceria-based nano-theranostic agent for rheumatoid arthritis. Theranostics, 10, 11863–11880. Kamat, S., & Kumari, M. (2023). Emergence of microbial resistance against nanoparticles: Mechanisms and strategies. Frontiers in Microbiology, 14, 1–9. https://doi.org/10.3389/ fmicb.2023.1102615 Kamat, S., Kumari, M., Sajna, K. V., Mohan, S., & Jayabaskaran, C. (2022). Marine endophytes from the Indian coasts: The untapped sources of sustainable anticancer drug discovery. Sustainable Chemistry and Pharmacy, 27, 100675. https://doi.org/10.1016/j.scp.2022.100675 Kampmann, T., Mueller, D. S., Mark, A. E., Young, P. R., & Kobe, B. (2006). The role of histidine residues in low-pH-mediated viral membrane fusion. Structure, 14, 1481–1487. https://doi. org/10.1016/j.str.2006.07.011 Khashan, K. S., Sulaiman, G. M., Abdulameer, F. A., Albukhaty, S., Ibrahem, M. A., Al-Muhimeed, T., & Alobaid, A. A. (2021). Antibacterial activity of TiO2 nanoparticles prepared by one-step laser ablation in liquid. Applied Sciences, 11, 4623. Khurana, A., Tekula, S., & Godugu, C. (2018). Nanoceria suppresses multiple low doses of streptozotocin-­induced type 1 diabetes by inhibition of Nrf2/NF-B pathway and reduction of apoptosis. Nanomedicine-UK, 13, 1905–1922. Kumar, K. M., Mahendhiran, M., & Diaz, M. C. (2018). Green synthesis of Ce3 + rich CeO2 nanoparticles and its antimicrobial studies. Materials Letters, 214, 15–19. https://doi.org/10.1016/j. matlet.2017.11.097 Kunga Sugumaran, V., Gopinath, K., & Palani, N. S. (2016). Plant pathogenic fungus F. solani mediated biosynthesis of Nanoceria: Antibacterial and antibiofilm activity. RSC Advances, 6, 42720–42729. Kwon, H. J., Cha, M., Kim, D., Kim, D. K., Soh, M., Shin, K., Hyeon, T., & Mook-Jung, I. (2016). Mitochondria-targeting ceria nanoparticles as antioxidants for Alzheimer’s disease. ACS Nano, 10, 2860–2870. Lee, J., Liao, H., Wang, Q., Han, J., Han, J. H., Shin, H. E., Ge, M., Park, W., & Li, F. (2022). Exploration of nanozymes in viral diagnosis and therapy. Exploration, 2(1), 20210086. Levy, S. B., & Marshall, B. (2004). Antibacterial resistance worldwide: Causes, challenges and responses. Nature Medicine, 10, 122–129. Liu, H., & Liu, J. (2020). Self-limited phosphatase-mimicking CeO2 nanozymes. Chem Nano Mat, 6, 947–952. Lord, M. S., Berret, J. F., Singh, S., Vinu, A., & Karakoti, A. S. (2021). Redox active cerium oxide nanoparticles: Current status and burning issues. Small, 17, 2102342. Matussin, S. N., & Khan, M. M. (2022). Phytogenic fabrication of CeO2@ SnO2 heterojunction nanostructures for antioxidant studies. Chemical Papers, 76(4):2071– 2084. Matussin, S. N., Harunsani, M. H., & Khan, M. M. (2023). CeO2 and CeO2-based nanomaterials for photocatalytic, antioxidant and antimicrobial activities. Journal of Rare Earths, 41(2), 167–181. Maqbool, Q., Nazar, M., & Maqbool, A. (2018). CuO and CeO2 nanostructures green synthesized using olive leaf extract inhibits the growth of highly virulent multidrug resistant bacteria. Frontiers in Pharmacology, 9, 987. https://doi.org/10.3389/fphar.2018.00987 Mccord, J. M., & Fridovic, I. (1969). Superoxide dismutase an enzymic function for erythrocuprein (hemocuprein). The Journal of Biological Chemistry, 244, 6049–6055. McNeilly, O., Mann, R., Hamidian, M., & Gunawan, C. (2021). Emerging concern for silver nanoparticle resistance in Acinetobacter baumannii and other bacteria. Frontiers in Microbiology, 12, 894. https://doi.org/10.3389/fmicb.2021.652863

198

A. Vijayan et al.

Mohamed, H. E. A., Afridi, S., Khalil, A. T., Ali, M., Zohra, T., Akhtar, R., Ikram, A., Shinwari, Z. K., & Maaza, M. (2020). Promising antiviral, antimicrobial and therapeutic properties of green nanoceria. Nanomedicine, 15, 467–488. https://doi.org/10.2217/nnm-­2019-­0368 Muduli, S., Behera, S. S., Mohapatra, R. K., Parhi, P. K., & Sahoo, T. R. (2023). Efficient adsorption and antimicrobial application of bio-synthesized porous CeO2 nanoparticles. Materials Science and Engineering: B, 290, 116275. https://doi.org/10.1016/j.mseb.2023.116275 Muhr, V., Wilhelm, S., Hirsch, T., & Wolfbeis, O. S. (2014). Upconversion nanoparticles: From hydrophobic to hydrophilic surfaces. Accounts of Chemical Research, 47(12), 3481–3493. Murray, C. J., Ikuta, K. S., Sharara, F., Swetschinski, L., Robles Aguilar, G., & Gray, A. (2022). Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet, 399, 629–655. https://doi.org/10.1016/S0140-­6736(21)02724-­0 Murali, A., Lan, Y. P., Sarswat, P. K., & Free, M. (2019). Synthesis of CeO2/reduced graphene oxide nanocomposite for electrochemical determination of ascorbic acid and dopamine and for photocatalytic applications. Materials Today Chemistry, 12, 222–232. Nadeem, M., Abbasi, B.  H., & Younas, M. (2017). A review of the green syntheses and anti-­ microbial applications of gold nanoparticles. Green Chemistry Letters and Reviews, 10(4), 216–227. https://doi.org/10.1080/17518253.2017.1349192 Nadeem, M., Tungmunnithum, D., & Hano, C. (2018). The current trends in the green syntheses of titanium oxide nanoparticles and their applications. Green Chemistry Letters and Reviews, 11(4), 492–502. https://doi.org/10.1080/17518253.2018.1538430 Nadeem, M., Khan, R., Afridi, K., Nadhman, A., Ullah, S., Faisal, S., Mabood, Z. U., Hano, C., & Abbasi, B. H. (2020). Green synthesis of cerium oxide nanoparticles (CeO2 NPs) and their antimicrobial applications: a review. International Journal of Nanomedicine, 11, 5951–5961. Nayem, S. M. A., Sultana, N., Haque, M. A., Miah, B., Hasan, M. M., Islam, T., Hasan, M. M., Awal, A., Uddin, J., Aziz, M. A., & Ahammad, A. J. S. (2020). Green synthesis of gold and silver nanoparticles by using Amorphophallus paeoniifolius tuber extract and evaluation of their antibacterial activity. Molecules, 25, 4773. Neal, C. J., Fox, C. R., Sakthivel, T. S., Kumar, U., Fu, Y., Drake, C., Parks, G. D., & Seal, S. (2021). Metal-mediated nanoscale cerium oxide inactivates human coronavirus and rhinovirus by surface disruption. ACS Nano, 15(9), 14544–14556. Nefedova, A., Rausalu, K., Zusinaite, E., Vanetsev, A., Rosenberg, M., Koppel, K., Lilla, S., Visnapuu, M., Smits, K., Kisand, V., Tatte, T., & Ivask, A. (2022). Antiviral efficacy of cerium oxide nanoparticles. Scientific Reports, 12, 18746. https://doi.org/10.1038/s41598-­022-­23465-­6 Nelson, B. C., Johnson, M. E., Walker, M. L., Riley, K. R., & Sims, C. M. (2016). Antioxidant cerium oxide nanoparticles in biology and medicine. Antioxidants, 5(2), 15. Pagnout, C., Razafitianamaharavo, A., Sohm, B., Caillet, C., Beaussart, A., & Delatour, E. (2021). Osmotic stress and vesiculation as key mechanisms controlling bacterial sensitivity and resistance to TiO2 nanoparticles. Communication Biology, 4, 1–15. https://doi.org/10.1038/ s42003-­021-­02213-­y Pirmohamed, T., Dowding, J. M., Singh, S., Wasserman, B., Heckert, E., Karakoti, A. S., King, J.  E. S., Seal, S., & Self, W.  T. (2010). Nanoceria exhibit redox state-dependent catalase mimetic activity. Chemical Communications, 46, 2736. Poon, W., Zhang, Y. N., Ouyang, B., Kingston, B. R., Wu, J. L., Wilhelm, S., & Chan, W. C. (2019). Elimination pathways of nanoparticles. ACS Nano, 13(5), 5785–5798. Prabakaran, A.  S., & Mani, N. (2019). Anti-inflammatory activity of silver nanoparticles synthesized from Eichhornia crassipes: An in vitro study. Journal of Pharmacognosy and Phytochemistry, 8(4), 2556–2558. Rocha, L. S. R., Simões, A. Z., Macchi, C. et al. (2022). Synthesis and defect characterization of hybrid ceria nanostructures as a possible novel therapeutic material towards COVID-19 mitigation. Sci Rep 12, 3341. https://doi.org/10.1038/s41598-022-07200-9 Sabeena, G., Rajaduraipandian, S., Pushpalakshmi, E., Alhadlaq, H. A., Mohan, R., Annadurai, G., & Ahamed, M. (2022a). Green and chemical synthesis of CuO nanoparticles: A comparative study for several in vitro bioactivities and in vivo toxicity in zebrafish embryos. Journal of King Saud University – Science, 34(5), 102092. https://doi.org/10.1016/j.jksus.2022.102092

Cerium Oxide Nanoparticles for Biomedical Applications

199

Sabeena, G., Rajaduraipandian, S., Bala, S.  P. M., Manju, T., Alhadlaq, H.  A., Mohan, R., Annadurai, G., & Ahamed, M. (2022b). In vitro antidiabetic and anti-inflammatory effects of Fe-doped CuO-rice husk silica (Fe-CuO-SiO2) nanocomposites and their enhanced innate immunity in zebrafish. Journal of King Saud University – Science, 34(5), 102121. https://doi. org/10.1016/j.jksus.2022.102121 Sabeena, G., Pushpalakshmi, E., Rajaduraipandian, S., & Annadurai, G. (2023). Novel super nanocomposite (CeO-SiO2 nanocomposite) with enhanced biological application: Synthesis and characterization. Plant Nano Biology, 3, 100025. Sebastiammal, S., Mariappan, A., Neyvasagam, K., & Fathima, A. L. (2019). Annona muricata inspired synthesis of CeO2 nanoparticles and their antimicrobial activity. Materials Today, 9, 627–632. Shcherbakov, A.  B., Zholobak, N.  M., Spivak, N.  Y., & Ivanov, V.  K. (2014). Advances and prospects of using nanocrystalline ceria in cancer theranostics. Russian Journal of Inorganic Chemistry, 59, 1556–1575. https://doi.org/10.1134/S003602361413004X Shcherbakov, A. B., Zholobak, N. M., & Ivanov, V. K. (2020). Biological, biomedical and pharmaceutical applications of cerium oxide. In Cerium oxide (CeO2): Synthesis, properties and applications (pp. 279–358). Elsevier. https://doi.org/10.1016/B978-­0-­12-­15661-­2.00008-­6 Shrivastava, S., Bera, T., & Roy, A. (2007). Characterization of enhanced antibacterial effects of novel silver nanoparticles. Nanotechnology, 18, 225103. Shydlovska, O., Kharchenko, E., Osenniy, I., Spivak, M., Shcherbakov, A., & Zholobak, N. (2018). Nanoparticles of cerium dioxide  – an effective antiviral agent and adjuvant of biologically active molecules. Science Rise: Biological Science, 1, 26–30. https://doi. org/10.15587/2519-­8025.2018.124686 Skirtach, A. G., Munoz Javier, A., Kreft, O., Köhler, K., Piera Alberola, A., Möhwald, H., Parak, W. J., & Sukhorukov, G. B. (2006). Laserinduced release of encapsulated materials inside living cells. Angewandte Chemie International Edition, 45(28), 4612–4617. Singh, N. B., Jain, P., De, A., & Richa Tomar, R. (2021). Green synthesis and applications of nanomaterials. Current Pharmaceutical Biotechnology, 22(13), 1705–1747. Siposova, K., Huntosova, V., Garcarova, I., Shlapa, Y., Timashkov, I., Belous, A., & Musatov, A. (2022). Dual-functional antioxidant and antiamyloid cerium oxide nanoparticles fabricated by controlled synthesis in water-alcohol solutions. Biomedicine, 10, 942. Sondi, I., & Salopek-Sondi, B. (2004). Silver nanoparticles as antimicrobial agent: A case study on E. coli as a model for Gram-negative bacteria. Journal of Colloid and Interface Science, 275, 177–182. Stabryla, L. M., Johnston, K. A., Diemler, N. A., Cooper, V. S., Millstone, J. E., & Haig, S. J. (2021). Role of bacterial motility in differential resistance mechanisms of silver nanoparticles and silver ions. Nature Nanotechnology, 16, 996–1003. https://doi.org/10.1038/s41565-­021-­00929-­w Stoimenov, P. K., Klinger, R. L., & Marchin, G. L. (2002). Metal oxide nanoparticles as bactericidal agents. Langmuir, 18, 6679–6686. Tang, G., He, J., Liu, J., Yan, X., & Fan, K. (2021). Nanozyme for tumor therapy: Surface modification matters. Exploration, 1(1), 75–89. Theuretzbacher, U. (2013). Global antibacterial resistance: The never-ending story. Journal of Global Antimicrobial Resistance, 1, 63–69. Tong, Y. N., Zhang, L. J., Gong, R., Shi, J. Y., Zhong, L., Duan, X. M., & Zhu, Y. X. (2020). A ROS-scavenging multifunctional nanoparticle for combinational therapy of diabetic nephropathy. Nanoscale, 12, 23607–23619. Triastuti, A., Zakiyyah, S. N., Gaffar, S., Anshori, I., Surawijaya, A., Hidayat, D., Wiraswati, H. L., Yusuf, M., Hartati, Y. W. (2003). CeO2@NH2 functionalized electrodes for the rapid detection of SARS-CoV-2 spike receptor binding domain. RSC Adv. Feb 16;13(9):5874–5884. https:// doi.org/10.1039/d2ra07560a Walls, A. C., Xiong, X., Park, Y. J., Tortorici, M. A., Snijder, J., Quispe, J., Cameroni, E., Gopal, R., Dai, M., & Lanzavecchia, A. (2019). Unexpected receptor functional mimicry elucidates activation of coronavirus fusion. Cell, 176, 1026–1039.

200

A. Vijayan et al.

Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 181, 281–292. Wang, M., He, H., Liu, D., Ma, M., & Zhang, Y. (2022). Preparation, characterization and multiple biological properties of peptide-modified cerium oxide nanoparticles. Biomolecules, 12(9), 1277. Wang, Q., Wang, B., Shi, D., Li, F., & Ling, D. (2023). Cerium oxide nanoparticles-based optical biosensors for biomedical applications. Advanced Sensor Research, 2(3), 2200065. Wasa, A., Aitken, J., Jun, H., Bishop, C., Krumdieck, S., & Godsoe, W. (2022). Copper and nanostructured anatase rutile and carbon coatings induce adaptive antibiotic resistance. AMB Express, 12, 1–10. https://doi.org/10.1186/s13568-­022-­01457-­z Watanabe, Y., Allen, J. D., Wrapp, D., McLellan, J. S., & Crispin, M. (2020). Site-specific analysis of the SARS-CoV-2 glycan shield. https://doi.org/10.1101/2020.03.26.010322 Wei, H., & Wang, E. (2013). Nanomaterials with enzyme-like characteristics (nanozymes): Next-­ generation artificial enzymes. Chemical Society Reviews, 42(14), 6060–6093. Weiss, C., Carriere, M., Fusco, L., Capua, I., Regla-Nava, J. A., Pasquali, M., Scott, J. A., Vitale, F., Unal, M. A., Mattevi, C., et al. (2020). Toward nanotechnology-enabled approaches against the COVID-19 pandemic. ACS Nano, 14, 6383–6406. Wu, J., Wang, X., Wang, Q., Lou, Z., Li, S., Zhu, Y., Qin, L., & Wei, H. (2019). Nanomaterials with enzyme-like characteristics (nanozymes): Next-generation artificial enzymes (II). Chemical Society Reviews, 48(4), 1004–1076. Xiang, D. X., Chen, Q., Pang, L., & Zheng, C. L. (2011). Inhibitory effects of silver nanoparticles on H1N1 influenza a virus in vitro. Journal of Virological Methods, 178, 137–142. Xu, P., Maidment, B. W., Antonic, V., Jackson, I. L., Das, S., Zodda, A., Zhang, X., Seal, S., & Vujaskovic, Z. (2016). Cerium oxide nanoparticles: A potential medical countermeasure to mitigate radiation-induced lung injury in CBA/J mice. Radiation Research, 185, 516–526. Yadav, S., Chamoli, S., Kumar, P., & Maurya, P. K. (2023). Structural and functional insights in polysaccharides coated cerium oxide nanoparticles and their potential biomedical applications: A review. International Journal of Biological Macromolecules, 3, 125673. Yang, W., Wang, L., Mettenbrink, E. M., DeAngelis, P. L., & Wilhelm, S. (2021). Nanoparticle toxicology. Annual Review of Pharmacology and Toxicology, 61, 269–289. Yefimova, S., Klochkov, V., Kavok, N., Tkachenko, A., Onishchenko, A., Chumachenko, T., Dizge, N., Özdemir, S., Gonca, S., & Ocakoglu, K. (2022). Antimicrobial activity and cytotoxicity study of cerium oxide nanoparticles with two different sizes. Journal of Biomedical Materials Research. https://doi.org/10.1002/jbm.b.35197 Yonathan, K., Mann, R., Mahbub, K. R., & Gunawan, C. (2022). The impact of silver nanoparticles on microbial communities and antibiotic resistance determinants in the environment. Environmental Pollution, 293, 118506. https://doi.org/10.1016/j.envpol.2021.118506 Zhang, M., Zhang, C., Zhai, X., Luo, F., Du, Y., & Yan, C. (2019). Antibacterial mechanism and activity of cerium oxide nanoparticles. Science China Materials, 62(11), 1727–1739. Zholobak, N. M., Olevinskaia, Z. M., Spivak, N. I., Shcherbakov, A. B., Ivanov, V. K., & Usatenko, A. V. (2010). Antiviral effect of cerium dioxide nanoparticles stabilized by low molecular polyacrylic acid. Mikrobiolohichnyi Zhurnal (Ukraine), 72, 42–47. Zholobak, N. M., Shcherbakov, A. B., Vitukova, E. O., Yegorova, A. V., Scripinets, Y. V., Leonenko, I., Baranchikov, A.  Y., Antonovich, V.  P., & Ivanov, V.  K. (2014). Direct monitoring of the interaction between ROS and cerium dioxide nanoparticles in living cells. RSC Advances, 4, 51703–51710. https://doi.org/10.1039/C4RA08292C Zholobak, N.  M., Mironenko, A.  P., Shcherbakov, A.  B., Shydlovska, O.  A., Spivak, M.  Y., Radchenko, L. V., Marinin, A. I., Ivanova, O. S., Baranchikov, A. E., & Ivanov, V. K. (2016). Cerium dioxide nanoparticles increase immunogenicity of the influenza vaccine. Antiviral Research, 127, 1–9. https://doi.org/10.1016/j.antiviral.2015.12.013

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances, Challenges, and Future Prospects Natarajan Sisubalan, Shalini Ramadoss, Muniraj Gnanaraj, Arumugam Vijayan, Karthikeyan Chandrasekaran, Sivamaruthi Bhagavathi Sundaram, Chaiyasut Chaiyavat, and Varaprasad Kokkarachedu

Overviews The advancement of nanotechnology in recent years has prepared the path for ground-breaking solutions in several industries, including healthcare and medicine. Utilizing metal oxide nanoparticles for their antimicrobial property is one such field N. Sisubalan (*) · C. Chaiyavat Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand S. Ramadoss Department of Botany, Bishop Heber College (Autonomous), Affiliated to Bharathidasan University, Tiruchirappalli, Tamil Nadu, India M. Gnanaraj Department of Biotechnology and Bioinformatics, Bishop Heber College (Autonomous), Tiruchirappalli, India A. Vijayan Department of Microbiology, SRM Institute of Science and Technology, Tiruchirappalli Campus, Tiruchirappalli, Tamil Nadu, India K. Chandrasekaran Department of Chemical and Biochemical Engineering, Dongguk University, Seoul, Republic of Korea S. Bhagavathi Sundaram Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand Office of Research Administration, Chiang Mai University, Chiang Mai, Thailand V. Kokkarachedu Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_9

201

202

N. Sisubalan et al.

of study. Particularly, magnesium oxide (MgO) nanoparticles have demonstrated remarkable promise for preventing the spread of germs and viruses. Unique bio/ physicochemical characteristics of MgO nanoparticles contribute to their antimicrobial action. Nanoparticles emit Mg2+ when they come into contact with water, which can disrupt bacterial and viral biological processes. The main modes of action for MgO nanoparticles include surface interaction, pH change, and oxidative stress. MgO nanoparticles have been effective against a variety of viruses and bacteria, including both Gram-positive and Gram-negative species. The ability to act broadly is essential for protection  against various diseases. MgO nanoparticles are less harmful to human cells than traditional antibacterial treatments, making them a potentially safe substitute. To fully hold their long-term benefits and potential hazards, however, more research is required. MgO nanoparticles can be created utilizing easy and affordable techniques, and they are generally stable. It increases their capacity for mass production and potential future commercialization. MgO nanoparticles have demonstrated a lesser propensity for resistance development in bacteria when compared to conventional antibiotics, which can result in the formation of antibiotic resistance in bacteria. In order to fight the growing issue of antibiotic resistance, this trait is essential. While the use of MgO nanoparticles to prevent the growth of bacteria and viruses shows promise, there are still a number of issues that need to be resolved, such as nanoparticle stability, biocompatibility, standardization, and regulation. A potentially useful family of antibacterial drugs, MgO nanoparticles, may be used to suppress bacteria and viruses. They are a topic of intense attention in the field of nanomedicine due to their distinct physicochemical properties, broad-spectrum efficacy, low toxicity, and qualities that help to mitigate resistance. To overcome obstacles and confirm their effectiveness and safety in various therapeutic contexts, more study is required. MgO nanoparticles could contribute significantly to the fight against infectious diseases and open the door for novel treatment approaches with further improvements.

Introduction The biocidal chemicals that can be triggered by both ultraviolet and visible spectra are used by multifunctional nanomaterials. According to Sisubalan et  al. (2018), multifunctional nanomaterials may be generated affordably, with excellent yield, tunable characteristics, a variety of uses, controllability, and quick results. However, there are integrated and selected inorganic and organic-biopolymer (chitosan) materials for nanotherapeutic dispensation that can be used to increase the medicinal properties of nanomaterials for the treatment of cancer and drug-resistant microorganisms (Karthikeyan et al., 2021; Sisubalan et al., 2021). One of the biocompatible, nontoxic, and secure inorganic compounds are magnesium oxide (MgO). Additionally, due to the presence of active oxygen (● O2− ) radicals in the aqueous solution, MgO nanoparticles (NPs) display a distinct biocidal property (Sawai et al.,

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

203

1997); (Sawai et al., 2000). However, reactive oxygen species (ROS), such as the hydroxyl radical, superoxide radical, and hydrogen peroxide, frequently damage deoxyribonucleic acid (DNA) and cellular proteins, and this results in the death of bacteria (Becker et al., 2011). This led to the use of MgO in the production of novel nanomaterials in place of cationic biopolymers in an effort to improve the medicinal characteristics of substances/agents that contain it. Due to their advanced physicochemical properties, MgO nanoparticles may also be used as a biocidal agent. Additionally, the biocidal capacity of the resulting MgO nanoparticles would be significantly increased if it were combined with any foreign impurities that also have strong antimicrobial and anticancer potentials due to the encapsulation of the substrate (chitosan) effect of the two distinct materials present in the nanoparticles’ composition. MgO is a naturally occurring, economically viable, and strategically significant NPs that stands out for its exceptional physicochemical characteristics. These include outstanding refractive index (Khan et  al., 2020; Ramezani Farani et  al., 2023), excellent corrosion resistance (Amaral et al., 2010), high thermal conductivity (Hornak et  al., 2018), excellent optical transparency (Wang et  al., 2017), mechanical strength (Zhao et  al., 2009), dielectric resistance (Shen et  al., 2020), stability (Pilarska et al., 2017), flame resistance (Ding et al., 2001), physical strength (Sain et al., 2004; Kipcak et al., 2014), and low electrical conductivity (Tang et al., 2013; Itatani et al., 2006; Khalil et al., 2020). MgO is used as a refractory material, photocatalyst, electrochemical biosensor, semiconducting material, absorbent of organic and inorganic pollutants from wastewater, and catalyst in organic transformations (Abinaya et al., 2021) based on the aforementioned properties. MgO NPs’ photocatalytic properties significantly contribute to the removal of environmental pollution and the antibacterial behavior of these NPs (Panchal et al., 2022). A widegap insulating metal oxide with 5–6 eV band energy is called MgO (Spagnoli et al., 2011). MgO is optically active for photocatalytic performance because its bandgap energy is high (i.e., >5  eV) (Sohrabi and Taleshi, 2014). Furthermore (Kumar & Kumar, 2008), MgO can produce reactive oxygen species (ROS) that can lead to oxidative stress in in vitro or in vivo cell lines, which can inhibit pathogenic activity. MgO NPs were recently made a tremendous inhibition rate against multidrug resistance (MDR) (Karthikeyan et  al., 2021), methicillin-resistant Staphylococcus aureus (MRSA) (Andrade et  al., 2023), and viruses (Noori & Kareem, 2019). Patients with hematological diseases have experienced significant mortality as a result of the COVID-19 pandemic brought on by the spread of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Passamonti et al., 2020). Amid the primary wave of widespread, patients with Philadelphia-negative constant myeloproliferative neoplasms (MPN) counting fundamental thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) were detailed at higher chance of securing SARS-CoV-2 and of having a destitute result after disease, with a mortality rate of approximately 30%, expanding to 48% in MF patients (Barbui et al., 2021). This book chapter provides insights into MgO nanoparticles in various aspects, viz. bactericidal/virucidal mechanism, advantages and disadvantages, recent progress and development, and future perspectives, respectively.

204

N. Sisubalan et al.

Advantages and Disadvantages Nanotechnology is a field of science concerned with the manufacture of nanoparticles with normal molecule sizes extending from 1 to 100  nm utilizing different blend strategies (Jamkhande et al., 2019; Kumar et al., 2023). Their minute dimensions, nanomaterials have one-of-a-kind highlights, such as astonishing electrical, mechanical, and thermal characteristics, an expansive surface zone, and great optical and attractive properties (Khoshnevisan et  al., 2019; Yaqoob et  al., 2020; Karthikeyan et al., 2022). Nanomaterials are being utilized in different areas these days, such as atomic science, material science, mechanical building, fabric science, and wastewater innovation (Heiligtag & Niederberger, 2013; De et  al., 2008). Various nanostructures and hybrid nanomaterials are currently being investigated by many researchers for the fabrication of composite polymers (Moura et al., 2017), disease diagnosis and treatment (Banerjee et al., 2017; Nandhini et al., 2023), sensor (Gomez-Romero, 2001; Shaikh et al., 2016), catalysis (Narayanan & El-Sayed, 2004), and labeling of optoelectronic recording media by their unique properties (Gracias et al., 2009). Magnesium oxide (MgO) nanoparticles offer several advantages by their unique properties and versatile applications. Here are some advantages of MgO nanoparticles: • • • • • • • • • •

Small particle size (Ahmad et al., 2023) High surface area (Goodarzi et al., 2023) Enhanced reactivity (Singh et al., 2023) Optical properties (Ahmad et al., 2023) Antibacterial and antimicrobial properties (Karthikeyan et al., 2021) Biocompatibility (Ebrahimi et al., 2023) Thermal stability (Azizi et al., 2023) Electrical insulation (Subash et al., 2023) Environmental friendliness (Ahmad et al., 2023) Versatility (Shanmugam et al., 2023)

MgO nanoparticles size allows for a larger surface area to volume ratio, resulting in increased reactivity and enhanced properties compared to bulk MgO materials. The high surface area of MgO nanoparticles provides more active sites for chemical reactions. This property is advantageous for various applications, including catalysis, where increased surface area enhances the catalytic activity. The high surface area and small size of MgO nanoparticles lead to enhanced reactivity compared to bulk MgO. This property makes them suitable for catalytic applications, such as in fuel cells, where they can accelerate chemical reactions efficiently. MgO nanoparticles exhibit unique optical properties, including high transparency in the electromagnetic spectrum’s visible and ultraviolet (UV) regions. It is  useful in optoelectronics, photocatalysis, and UV shielding applications. MgO nanoparticles have demonstrated antibacterial and antimicrobial activity against various pathogens  (Karthikeyan et  al., 2021). They can be used in medical and

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

205

healthcare applications, including wound healing, drug delivery, and antimicrobial coatings. MgO nanoparticles are generally considered biocompatible, meaning they have minimal toxic effects on living cells. This property is valuable in biomedical applications, such as drug delivery systems and bioimaging. MgO nanoparticles possess excellent thermal stability, making them suitable for high-temperature applications. It is used as fillers or reinforcements in materials to enhance their thermal properties. MgO nanoparticles exhibit excellent electrical insulation properties and incorporated into polymers, ceramics, and other materials to improve electrical insulation, which is advantageous for electronic devices and insulation coatings. MgO is an environmentally friendly material, as it is abundant in nature and does not contain toxic elements. This aspect makes MgO nanoparticles attractive for various sustainable applications. MgO nanoparticles find applications in a wide range of fields, including catalysis, electronics, energy storage, sensors, environmental remediation, and biomedicine. Their versatile nature makes them adaptable to various industries and research areas (Fernandes et al., 2020). Nanoparticle derived from MgO can be used in many ways including helping clean up the environment, making chemical reactions happen faster, and even creating energy. Small green particles of MgO can be made without any harm using substances from different types of living things like plants, fungi, bacteria, algae, and lichens. They showed interesting and special characteristics in their shape, how much surface they have, how small they are, and how they stay in place. Green nanoparticles made of MgO can be used to fight germs, soak up substances, detect colors, and have a lot of potential for medical treatments like cancer, diseases, and detecting dopamine  (Javed et  al., 2023). Green MgO particles are important for plants because they can help with things like getting rid of harmful things in the soil, growing plant cells and organs, and helping seeds sprout. All of this is very helpful for farming (Fig. 1: adapted from Nguyen et al., 2023). The utilization of magnesium oxide nanoparticles offers numerous benefits, including minimal harm to plants, resistance to high temperatures, absence of genetic toxicity, and safety for humans. These advantages allow for promising possibilities in the field of plant preservation (Singh, 2017). In addition to the mentioned features, nanoparticles possess several other qualities that enable them to have significant applications in various agricultural fields, as depicted in Fig.  2. Moreover, these nanoparticles have demonstrated their ability to boost peanut yield through their positive impact on seedling and plant growth. Additionally, these particles are being applied as authorized food coloring agents, supplements, additives, and more (Singh, 2019; Ganapathi Rao et al., 2014). Contamination of the environment is a significant concern encountered by both developed and developing countries worldwide. Numerous methods exist to address environmental pollution; however, the downside stems from the adverse effects that the cleaning agents can have once they behave as a harmful substance. Nanoparticles have become a highly effective substitute for other methods of promoting environmental hygiene. The diverse range of properties exhibited by MgO nanoparticles have enabled them to quickly establish a successful presence in numerous environmental applications (Fig. 3; recreated from Fernandes et al., 2020) by the diverse

206

N. Sisubalan et al.

Fig. 1  Source of MgO nanoparticle synthesis and overview of its applications. (Adapted from Nguyen et al., 2023)

Fig. 2  Overview of the agricultural applications of MgO nanoparticles. (Recreated from Fernandes et al., 2020)

range of properties it exhibits. MgO nanoparticles are being utilized for their significant ability to absorb toxic gases such as nitrogen dioxide and sulfur dioxide due to their vast surface area and strong response capability (Liang et al., 2004; Camtakan et al., 2012; Park et al., 2006; Štengl et al., 2003; Yu et al., 2004).

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

207

Fig. 3  Environmental applications of MgO nanoparticles. (Recreated from Fernandes et al., 2020)

MgO nanoparticles offer various advantages in terms of their unique properties and potential applications. However, they also have a few disadvantages that should be considered. Some of the disadvantages of MgO nanoparticles include the following: Expensive (Aboyewa et al., 2021; Nguyen et al., 2023): The production of high-­ quality MgO nanoparticles can be expensive, especially when using sophisticated synthesis methods and limit their widespread use and application in various industries. Agglomeration (Zhou et al., 2011; Ouraipryvan et al., 2009): MgO nanoparticles have a tendency to agglomerate or cluster together, forming larger particles. It reduces their surface area and hinder their effectiveness in certain applications. Preventing agglomeration requires special handling and stabilization techniques. Toxicity (Abinaya et al., 2021): While MgO is generally considered safe, the toxicity of MgO nanoparticles can vary depending on their size, shape, and surface characteristics. In addition, it depends on its concentration. Some studies suggest that exposure to certain forms of MgO nanoparticles may have negative health effects, particularly in high concentrations or when inhaled. Surface Reactivity: MgO nanoparticles are highly reactive due to their high surface area. This reactivity can lead to unwanted side reactions or instability in certain applications. It may require additional steps or coatings to control the surface reactivity and maintain stability. Limited Dispersibility (Huang et  al., 2018): Achieving a stable dispersion of MgO nanoparticles in certain solvents or matrices can be challenging. Their tendency to agglomerate and their hydrophilic nature can hinder their dispersibility, making it difficult to achieve uniform dis-

208

N. Sisubalan et al.

tribution in certain systems. Size Control (Mughal et al., 2021): Controlling the size and size distribution of MgO nanoparticles during synthesis can be challenging. Achieving precise control over particle size is crucial for many applications, and variations in size can affect the properties and performance of MgO nanoparticles. It is important to note that the disadvantages mentioned above can be mitigated or overcome through careful synthesis techniques, surface modifications, and appropriate handling and application methods. Researchers continue to work on improving these aspects to enhance the performance and usability of MgO nanoparticles.

Toxicity Effect (a Mechanism) on Living Cells As the utilization of synthetic nanoparticles becomes more prevalent in the field of biology, growing apprehensions regarding their safety in human applications are coming to the forefront (Farah & Farah, 2019; Zhu et al., 2019). It shows how many of their characteristics, including their size (Elsaesser & Vyvyan Howard, 2012), morphology, surface functional groups (Renero-Lecuna et  al., 2019), and dose-­ dependent qualities (Chaicherd et al., 2019), may make them poisonous to healthy, normal human cells, tissues, and organs. Biosynthesized nanoparticles, which have harmless surface functional groups, pose less risk to human cells compared to chemically synthesized particles that incorporate synthetic chemicals as surface functional and capping agents (Jeevanandam et al., 2016). While certain nanoparticles that are produced biologically may pose a potential threat by interacting with cells, disintegrating into smaller particles, or clustering together (Naz et al., 2020; Roy et al., 2015). The toxicity of MgO nanoparticles in humans depends on various factors, including their size, shape, surface charge, concentration, duration of exposure, and route of exposure. While MgO nanoparticles are generally considered to have low toxicity, it is important to note that any nanomaterial can potentially pose health risks. Several studies have been conducted to assess the toxicity of MgO nanoparticles. In general, the toxicity of MgO nanoparticles appears to be relatively low compared to other nanoparticles, but some concerns have been raised. Inhalation: Inhalation is one potential route of exposure to MgO nanoparticles, especially in occupational settings. High concentrations of MgO nanoparticles in the air may cause respiratory irritation and lung inflammation. However, it is worth noting that these effects are primarily observed at high exposure levels, typically exceeding the recommended occupational exposure limits (Mahmoud et al., 2016). Exposure to MgO nanoparticles resulted in a dose-dependent increase in the presence of interstitial lymphocytes, lymphoid accumulation, congested and expanded blood vessels, peribronchiolar infiltration of lymphocytes, granulomatous reactions, and the appearance of alveolar macrophages after 24 h. The same effects

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

209

Fig. 4  Light micrograph of lung tissue from rats exposed to MgO (5 mg/kg) (a) at 1 day post-­ instillation periods (b) at 1 week post-installation periods (c) at 1 month post-installation periods. (Recreated from Gelli et al., 2015)

were reported after 1 week of exposure, but they declined and improved after one month, which supports the conclusion that MgO caused lung damage similar to that caused by quartz nanoparticle (Fig. 4). Based on their findings, it was indicated that the introduction of MgO nanoparticles into the airway caused a notable rise in the levels of pulmonary enzymes, which was corroborated by histopathological evaluations, indicating that MgO nanoparticles have toxic effects on the lungs (Gelli et al., 2015). Dermal Exposure: Limited studies suggest that dermal exposure to MgO nanoparticles is relatively safe, with no significant toxicity reported (Attayil Sukumaran et al., 2022). However, prolonged or repeated exposure to high concentrations may cause skin irritation in some individuals. Oral Exposure: Ingestion of MgO nanoparticles are a less common route of exposure. Studies on the oral toxicity of MgO nanoparticles are limited, but available evidence suggests low toxicity (Gerloff et al., 2009; Krishnamoorthy et al., 2012; García-Rodríguez et al., 2022). However, it is important to note that ingestion of large amounts of any solid material can cause digestive discomfort and obstruction. Systemic Toxicity: Some studies have indicated that MgO nanoparticles can enter the bloodstream and accumulate in organs such as the liver and kidneys. However, the toxicological implications of this accumulation are not well understood, and further research is needed to determine the long-term effects. It is important to exercise caution when working with nanoparticles in general. Proper safety measures, such as the use of personal protective equipment and adherence to recommended exposure limits, should be followed to minimize potential risks.

210

N. Sisubalan et al.

The consequential influence of plants are noteworthy, given their ability to conduct photosynthesis and subsequently emit oxygen into the air. Plants are likely to be affected to a greater extent by NPs pollutants than other organisms, as every single part of their structure, including their roots, leaves, and branches, interacts closely with the surrounding matrix of air, water, and soil. The leaves’ stoma permit air-borne NPs to enter the plant, whereas NPs from water and soil are more efficiently absorbed by the roots (Wang et al., 2013). Research has demonstrated that NPs pose a threat to the well-being of plants by hindering their development and impeding growth. The main factor responsible for the toxicity of plants are the generation of ROS, causing lipid peroxidation and harm to DNA, leading to a reduction in the amount of protein, photosynthetic pigments, and overall biomass (Kumar et al., 2023). While plants utilize enzymatic and nonenzymatic antioxidants to combat oxidative stress, these defense mechanisms may become less effective in environments with elevated levels of oxygen (Verma et al., 2018). Currently, finding an equilibrium between the beneficial healing properties of NPs and the unfavorable poisonous outcomes poses a challenge for scientists (Sukhanova et al., 2018; Wang et al., 2022). In their research, it was proven that Phytophthora infestans can be efficiently inhibited by MgO NPs (50 mg/L) through direct actions. They were able to reduce the severity of potato late blight without showing any apparent harmful impacts on the potatoes (Fig. 5). The mode of toxicity of MgO nanoparticles against P. infestans was elucidated by examining alterations in cell surface structure, detecting antioxidant activity, and carrying out transcriptomic analysis [Wang et al., 2022].

Antimicrobial Characteristics In the context of MgO nanoparticles and their potential inhibition of viral activity, several mechanisms have been proposed (Scheme 1); MgO nanoparticles can interact with viral proteins or host cell receptors, preventing the virus from attaching to the host cell and entering it, which disrupts the viral attachment. It may interfere with viral replication processes by inhibiting key enzymes or interfering with the viral genetic material, thereby reducing viral replication. MgO nanoparticles possess antioxidant properties and can modulate the immune response. This may help reduce the excessive inflammation and oxidative stress caused by viral infection, supporting the immune system’s ability to control the virus. MgO nanoparticles may directly interact with the viral envelope or capsid, disrupting their structure and rendering them noninfectious. The mechanisms of MgO, as it involves antibacterial efficacy, occur in diverse ways (Table 1), such as (a) direct interaction with the cell wall of bacteria, (b) ROS generation, and (c) initiation of intracellular defects, e.g., macromolecular interaction, such as proteins and/or DNA (Karthikeyan et al., 2021). A schematic view of the mechanism of chitosan magnesium oxide (CMgO) NPs is shown in Scheme 2.

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

211

Fig. 5  Effect of the MgO NPs on the antioxidant system and phenylalanine ammonia-lyase (PAL) activity. (a) superoxide dismutase (SOD) activities of P. infestans after 1, 3, and 6 h of MgO NPs or sterile water (CK) exposure. (b) catalase (CAT) peroxidases (POD) and POD activities of potato after 6 h of MgO NPs or sterile water (CK) exposure. (c) PAL activity of potato after 6 h of MgO NPs or sterile water (CK) exposure (adapted from Wang et al., 2022). This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)

Scheme 1  Virucidal mechanism of MgO nanoparticles

Recent Reports/Studies on COVID-19 Applications Magnesium (Mg) is a vital element found in small amounts in our bodies, and it plays a significant role in various physiological, biochemical, and cellular processes (Fanni et al., 2021). It is the second most abundant positively charged particle (cation) in cells, right after potassium. Almost all of the Mg in our bodies (about 99%) is found inside cells, with only around 1% in the blood and other fluids outside the cells (Schuchardt & Hahn, 2017; Konrad et al., 2004). Mg is involved in a wide

212

N. Sisubalan et al.

Table 1  Antibacterial mechanism of MgO NPs doped with different combinations against various bacterial strains Bacterial S.no. Nanomaterial name 1 Ag-MgO E. coli

Size and morphology 40-nm grainy particles

2

Cu-MgO

S. aureus, E.coli

The high level of the zone of inhibition was measured in the Cu-doped MgO NPs against low concentrations

3

Ag-MgO

E. coli and K. pneumonia

16 ± 2, 15 ± 2 nm uniform distribution of spherical particles, small berries like morphologies, and crystal structure of periclase 16.44 nm

4

Cu-MgO

S. aureus, E.coli

50 nm, spinel structure, and cubic MgO in the material

23.4 ± 0.4, 21.2 ± 0.3, 32.6 ± 0.4, 32.4 ± 0.4

Efficiency in mm 10.33 ± 0.33 μM

13mm and 10 mm in dimension of irregular flake-like shapes, but upon ultrasound exposure, highly fine discrete spherical shapes resulted

Mechanism ROS generation led to the death of the bacterial cell, and the Ag-MgO composite had the ability of a larger generation of ● O− 2 (Zhu et al., 2016) The inhibition of bacterial cell amplification and the destruction of cells were, done by pure Cu-coated MgO NPs led to cell death (Rajendran et al., 2018).

Bacterial cell death was achieved by the penetration of Ag and Mg NPs into the bacterial genome and cellular enzymes from the Ag-MgOnHaP nanocomposites (Ayinde et al., 2018). The penetration of Cu+ and Cu2+ ions in the MgO lattice, induced the generation of oxygen vacancies and the copper (leaching) ions into the solution. These allow the Cu-doped MgO to have better antibacterial activity than the pure MgO (Zhang et al., 2018).

(continued)

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

213

Table 1 (continued) Bacterial S.no. Nanomaterial name 5 Ca-MgO E. coli, Eu-MgO P. aeruginosa, B. cereus, S. aureus

6

Ag-MgO

E. coli, S. aureus

7

Li-MgO

E. coli, S. aureus

Size and morphology 50–70 nm granular spherical NPs

Efficiency in mm Ca-MgO 12.26 ± 0.48, 13.98 ± 0.70, 12.63 ± 0.21, 10.56 ± 0.21 Eu-MgO 11.82 ± 0.19, 12.01 ± 0.65, 14.21 ± 0.81, 13.39 ± 0.43

Mechanism Eu3+-coated MgO NPs have reflected in the augmentation of the positive electrode enactment and, therefore, enhanced the electrochemical activities of the MgO NPs, leading to the improved antibacterial activity (Raveesha et al., 2019). 45-nm, 15 mm and 14 mm Enhanced ROS were produced by the cauliflower-­ intensified adsorbed shaped oxygen on the nanoparticles surface of MgO defect sites, resulting in the improved antibacterial activity of the Ag/MgO nanocomposites synthesized (Jayapriya et al., 2020). Bactericidal rates Li-doped MgO NPs 50-nm to showed admirable 150-nm, diverse for E. coli were molar contents 75.3%, 99.9%, and antibacterial performance by showed diverse 99.9% and for S. mechanical damage shapes by MgO aureus were and ROS damage 72.7%, doped with Li 99.5%, and 99.9%, (Tian et al., 2020). respectively

Adapted from Karthikeyan et al. (2021)

range of essential functions, such as helping in bone formation, supporting neuromuscular activity (the interaction between nerves and muscles), participating in signaling pathways within cells, contributing to energy production (bioenergetics), and aiding in the metabolism of glucose, lipids (fats), and proteins. Additionally, Mg is essential for maintaining the stability of DNA and RNA, the genetic material in our cells, and it also plays a role in cell growth and specialization. More than 600 enzymes in our bodies rely on Mg to function properly, and there are around 200 other enzymes where Mg helps activate their activities (Rubin, 2005; Kubota et al., 2005; Iotti et al., 2005; Feeney et al., 2016; Li et al., 2011; Fiorentini et al., 2021; Sargenti et al., 2018; Mammoli et al., 2019; Caspi et al., 2020).

214

N. Sisubalan et al.

Scheme 2  Schematic view of the antibacterial mechanism of CMgO NPs. (Adapted from Karthikeyan et al., 2021)

Mg has also been shown to be important for the proper functioning of our immune system, blood vessels, and lungs (Dominguez et al., 2021). It is necessary for the normal activities of immune cells like neutrophils, macrophages, and T lymphocytes, which are essential for fighting infections (Brandao et al., 2013; de Jesus et al., 2022). Mg also seems to have a role in inhibiting the replication of certain viruses. Notably, Mg has been linked to regulating both the innate and adaptive immune systems, which could have potential protective effects against illnesses like COVID-19. In short, Mg is a crucial element that influences various processes in our bodies, from bone health to immune system function. It helps many enzymes work correctly and has a role in supporting the body’s defenses against infections like COVID-19 (Guerrero-Romero et al., 2023). Likewise, studies conducted worldwide have shown that magnesium exhibits antioxidant and anti-inflammatory properties, which are beneficial in mitigating lung injury (Scheme 3). Additionally, magnesium sulfate effectively hinders airway smooth muscle contraction by blocking voltage-dependent calcium channels. This mechanism further establishes magnesium as a potential treatment option for asthma (Tang et al., 2020). Magnesium offers a broad range of benefits, and when supplemented within safe blood concentration levels, it can effectively prevent the development of disorders or diseases. Considering appropriate use, monitoring of serum magnesium levels, and control of essential cofactors and modulators, timely magnesium supplementation can be advantageous for COVID-19 patients with minimal side effects. However, further research with more clinical evidence is necessary to determine whether combining magnesium sulfate with other recommended treatment drugs would be more beneficial for COVID-19 patients during this unique outbreak. Additionally, some studies have highlighted the importance of trace elements like

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

215

Scheme 3  Possible mechanisms of magnesium supplementation reduce inflammation, oxidative stress, and bronchial smooth muscle relaxation. (Adapted from Tang et al., 2020)

magnesium, vitamins, and other nutrients in supporting the immune system and fighting against COVID-19 (Calder et al., 2020; Wallace, 2020; Tang et al., 2020).

Recent Studies on Antimicrobial and Antiviral Applications The distinctive physical and chemical properties of MgO nanoparticles, such as their ability to degrade, compatibility with biological organisms, positively charged capacity, high stability, and redox functions, have made them a promising substance for numerous biomedical uses. MgO nanoparticles are an appealing tool in the battle against harmful microorganisms and can potentially be a viable solution to address the difficulties involved in eradicating biofilms and antibiotic resistance. Thus, with the growing utilization of MgO nanoparticles in the field of biomedicine, novel techniques for their synthesis are imperative. Green synthesis or biosynthesis techniques have been used to create MgO nanoparticles that possess exceptional stability and can be employed in a diverse array of biological, medical, and catalytic applications, while also being deemed safe and environmentally friendly. This critique outlines the latest progress in the creation methods of MgO nanoparticles utilizing various biological templates such as plants, bacteria, fungi, and algae extracts (Ramezani Farani et al., 2023). MgO finds application as a refractory material, photocatalyst, electrochemical biosensor, semiconductor, absorbent for both organic and inorganic pollutants in

216

N. Sisubalan et al.

wastewater, and a catalyst for organic reactions, based on its described properties (Abinaya et al., 2021). Photocatalytic properties of MgO NPs play a significant role in removing the environmental pollution and antibacterial behavior of these NPs (Panchal et al., 2022). MgO is an insulating metal oxide that has a wide gap with a band energy of 5–6  eV (Spagnoli et  al., 2011). MgO possesses a high bandgap energy that exceeds 5 eV, rendering it effectively optically active for achieving photocatalytic performance (Sohrabi & Taleshi, 2014). Additionally, the production of reactive oxygen species (ROS) by MgO may result in oxidative stress in cell lines both in vitro and in vivo, ultimately resulting in antipathogenic effects (Kumar & Kumar, 2008). A range of techniques have been employed to produce nanoparticles for different purposes, such as medical uses, energy generation, environmental protection, and agricultural purposes. Recent developments in chemical methods utilized for crafting nanomaterials have heightened potential risks to both living organisms and the environment, owing to the employment of dangerous substances such as poisonous chemicals and heavy metals, including MgO, which are incorporated into the resulting nanomaterials (Farani et al., 2022; Ray et al., 2009; Prasanth et al., 2019). The biological synthesis of nanomaterials offers noteworthy benefits over physical and chemical methods due to its excellent biocompatibility and efficient synthesis process that does not require high energy consumption (Meng et al., 2020). Therefore, the use of biological sources for the synthesis of nanomaterials have increased significantly, such as plants (Akhavan et al., 2014), algae (Khan et al., 2022), and bacteria (Chellamuthu et al., 2018). One can use naturally occurring substances such as vitamins, polyphenols, polysaccharides, amino acids, biomolecules, and phytochemicals to function as chemical stabilizers and reduce the need for harmful chemicals (Adil et al., 2015; Nejati et al., 2021). Green methods have been widely developed for the synthesis of MgO NPs using energy-efficient, cost-effective, and eco-friendly manners (Fouda et al., 2020; Nguyen et al., 2023). The toxicity of MgO NPs toward biological systems are considerably influenced by various aspects such as NP size, biodegradability, shape, surface adsorption capacity, high surface charge, and high thermal stability, all of which contribute to their antimicrobial activity. Khan et al. (2020), utilized Dalbergia sissoo extract to create MgO NPs through biosynthesis and proceeded to analyze their antimicrobial properties and ability to act as a photocatalyst. Ramezani Farani et al. (2023) examined the effectiveness of MgO nanoparticles in breaking down methylene blue dye through photolysis. The highest efficiency for degrading MB dye was achieved by synthesizing MgO NPs with a lower band gap energy of 4.1 eV, resulting in an 81% photodegradation efficacy. Furthermore, the disk diffusion technique assessed the effectiveness of MgO NPs against bacteria. Assessments indicated that MgO NPs) possessing lower bandgap values exhibit superior antibacterial efficacy against E. coli and R. solanacearum bacterial strains in comparison to MgO NPs with higher bandgap values (Ramezani Farani et al., 2023). MgO nanoparticles exhibit distinct characteristics beneficial for dental purposes, particularly as potential bacteria-fighting agents. Their exceptional properties encompass effective suppression of cariogenic microorganisms. The glass ionomer

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

217

cement (GIC), modified with MgO nanoparticles, exhibited notable antibacterial and antibiofilm properties against microbes that cause caries (Noori & Kareem, 2019). The pathogenic bacterial strains, namely Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Klebsiella pneumoniae, were subjected to analysis to determine the potential antibacterial activity. Furthermore, the information presented indicates that the ability of MgO nanoparticles to inhibit is reliant on the concentration (Abinaya & Kavitha, 2023). The research on the antibacterial properties of chitosan-based MgO (CMgO). NPs demonstrated that they outperformed the commonly used antibiotic amoxicillin in terms of effectiveness. Furthermore, both the MgO and CMgO nanoparticles revealed the potential to induce cell death in human breast cancer cells. When the toxicity of CMgO NPs was compared to that of MgO NPs, it was observed that CMgO NPs exhibited lower toxicity toward healthy cells such as fibroblast L929. The potential applications of CMgO NPs in clinical settings are varied, including the treatment of pneumonia, bloodstream and urinary tract infections, kidney failure, and, particularly, wound infections (Karthikeyan et al., 2021). Epidemiologically concern, viruses are the most commonly occurring pathogens that have the potential to cause outbreaks. Occasionally, these animal reservoirs can lead to epidemics among humans (Bloom & Cadarette, 2019). Out of fourteen major global outbreaks that occurred over the past 120 years, eleven were caused by viruses. This is a significant reason for the heightened interest in nanoparticles as a means of tackling these pathogens. Furthermore, various viruses are responsible for widespread illnesses like the common cold, resulting in significant economic losses and severe health consequences, including morbidity and even mortality (Klepser, 2014). Respiratory viruses are the main cause of mortality worldwide causing up to 2.7 million deaths in 2015 alone (Troeger et  al., 2017). Lower respiratory tract infections are commonly caused by various viruses, with influenza A and B, metapneumovirus, parainfluenza virus (1–4), rhinovirus, enterovirus, and syncytial respiratory virus being the primary culprits. Other contributing viruses include several types of coronavirus, such as human coronavirus HKU1, human coronavirus NL63, human coronavirus OC43, mouse hepatitis virus strain E229, Middle East respiratory syndrome (MERS), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Giraud-Gatineau et al., 2020). The contributions that can be added by nanomedicine related to SARS-CoV-2 are noteworthy. This virus is emerging as a huge threat to healthcare and the economy in the whole world (Gurunathan et al., 2020) and has caused 676,609,955 million cases and at least 6,881,955 (https://coronavirus.jhu. edu/map.html) million deaths up to date. The main nanotechnological approach can be grouped into diagnosis technologies, vaccines, and possible therapies (Medhi et al., 2020). An intriguing method involves creating angiotensin-converting enzyme 2 (ACE2)-coated or embedded nanoflowers or quantum dots that can be incorporated into everyday items such as chewing gum, nose filters, masks, gloves, and clothes. This would effectively neutralize and reduce the spread of SARS-2 (Aydemir & Ulusu, 2020).

218

N. Sisubalan et al.

Future Prospects of MgO Nanoparticles MgO nanoparticles have a range of potential future prospects in various fields. Here are some possible areas where MgO nanoparticles could find applications: Biomedical Applications: MgO nanoparticles have shown promise in biomedical applications such as drug delivery systems, imaging agents, and therapeutics. They can be functionalized with specific ligands or biomolecules to target specific cells or tissues, making them useful in targeted therapy and diagnostics. Environmental Remediation: MgO nanoparticles have been investigated for their potential in environmental remediation, particularly in water treatment. They have shown effectiveness in removing heavy metals and organic pollutants from contaminated water sources. MgO nanoparticles’ high surface area and reactivity make them suitable for such applications. Catalysis: MgO nanoparticles can act as catalysts in various chemical reactions due to their unique surface properties. They can potentially be used in industrial processes to improve reaction rates, selectivity, and efficiency. Additionally, MgO nanoparticles can be used in catalytic converters for automotive applications to reduce harmful emissions. Energy Storage: MgO nanoparticles have been explored for energy storage applications, particularly in batteries and supercapacitors. They can be used as electrode materials or as components in composite materials to enhance the performance of energy storage devices. MGO nanoparticles have shown promise in improving battery capacity, cycling stability, and overall energy efficiency. Electronics and Optics: MgO nanoparticles have optical and electronic properties that make them attractive for applications in electronics and optics. They can be utilized in electronic devices, sensors, and optoelectronic devices such as light-­ emitting diodes (LEDs) and photodetectors. It is important to note that the future prospects of MgO nanoparticles depend on continued research and development, as well as advancements in nanotechnology. While these potential applications show promise, further studies are needed to optimize their properties, enhance their stability, and ensure their safety for widespread use.

Conclusion Metal oxide nanoparticles exhibit various properties such as antibacterial, antiviral, antifungal, and antibiofilm effects. The use of chemical synthesis methods for producing MgO NPs presents two problems, namely, poor biocompatibility and the formation of harmful substances that could adversely affect the environment. The demand for eco-friendly technique has led to an increase in the knowledge and utilization of greener chemistry to produce various nanoparticles through alternative routes. Four distinct approaches are employed by plants, fungi, bacteria, and algae to generate MgO nanoparticles. These NPs show great promise in the field of

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

219

biology and maybe a suitable alternative to chemically made NPs in the future. However, their long-term toxicity, diffusion, absorption, and excretion mechanisms are not fully understood. The methods rely mainly on the metabolites produced by biological materials and their extracts, which lead to the stabilization and capping of particles, resulting in the formation of nanoparticles. Several factors such as pH, extraction ratio, and temperature significantly impact the size, stability, shape, and surface area of MgO nanoparticles. Green methods or biomethods of synthesizing nanoparticles are eco-friendly and nontoxic to living organisms and have potential advantages in the biological field for practical purposes. Even though electrostatic contact and physical damage play important roles, the primary reason why these NPs have antibacterial property is due to the disruption of cell walls or membranes and the generation of ROS. Overall, MgO nanoparticles created via eco-friendly synthesis hold promise as effective agents against pathogens and are particularly well-suited for biomedical uses due to their biocompatibility and eco-friendliness. This chapter aims to comprehensively explain the process involved in creating efficient MgO NPs for future industrial and biological uses. Through genetic modification of plant sources, it is feasible to control the configuration, uniformity, and resilience of NPs. To obtain a comprehensive assessment of the antioxidant potential of biogenic MgO NPs, it is necessary to conduct further research either in vitro or in vivo. Further studies are required to evaluate the potential uses of MgO nanoparticles for the betterment of society. Acknowledgement  Authors SB, BSS, and CC are thankful to Chiang Mai University for the support, and SB thankfully acknowledges the CMU postdoctoral fellowship for its support. GM and SR greatly acknowledge the Bishop Heber College (Autonomous), Tiruchirappalli, Tamil Nadu, India, for providing physical facilities. Conflict of Interest  There is no conflict of interest to declare.

References Abinaya, S., & Kavitha, H. P. (2023). Magnesium oxide nanoparticles: Effective antilarvicidal and antibacterial agents. ACS Omega, 8(6), 5225. Abinaya, S., Kavitha, H. P., Prakash, M., & Muthukrishnaraj, A. (2021). Green synthesis of magnesium oxide nanoparticles and its applications: A review. Sustainable Chemistry and Pharmacy, 19, 100368. Aboyewa, J. A., Sibuyi, N. R., Meyer, M., & Oguntibeju, O. O. (2021). Green synthesis of metallic nanoparticles using some selected medicinal plants from Southern Africa and their biological applications. Plants, 10(9), 1929. Adil, S. F., Assal, M. E., Khan, M., Al-Warthan, A., Siddiqui, M. R. H., & Liz-Marzán, L. M. (2015). Biogenic synthesis of metallic nanoparticles and prospects toward green chemistry. Dalton Transactions, 44, 9709–9717. Ahmad, A., Khan, M., Khan, S., Luque, R., Almutairi, T.  M., & Karami, A.  M. (2023). Bio-­ construction of MgO nanoparticles using Texas sage plant extract for catalytical degradation

220

N. Sisubalan et al.

of methylene blue via photocatalysis. International Journal of Environmental Science and Technology, 20(2), 1451–1462. Akhavan, O., Bijanzad, K., & Mirsepah, A. (2014). Synthesis of graphene from natural and industrial carbonaceous wastes. RSC Advances, 4, 20441–20448. Amaral, L., Oliveira, I., Salomão, R., Frollini, E., & Pandolfelli, V. (2010). Temperature and common-­ ion effect on magnesium oxide (MgO) hydration. Ceramics International, 36, 1047–1054. Andrade, S., Ramalho, M. J., Santos, S. B., Melo, L. D., Santos, R. S., Guimarães, N., Azevedo, N. F., Loureiro, J. A., & Pereira, M. C. (2023). Fighting methicillin-resistant Staphylococcus aureus with targeted nanoparticles. International Journal of Molecular Sciences, 24(10), 9030. Attayil Sukumaran, S., Kalimuthu, B., Selvamurugan, N., & Mani, P. (2022). Wound dressings based on chitosan/gelatin/MgO composite films. International Journal of Polymeric Materials and Polymeric Biomaterials, 71(16), 1252–1261. Aydemir, D., & Ulusu, N. N. (2020). Correspondence: Angiotensin-converting enzyme 2 coated nanoparticles containing respiratory masks, chewing gums and nasal filters may be used for protection against COVID-19 infection. Travel Medicine and Infectious Disease, 37, 101697. Ayinde, W., Gitari, W., Munkombwe, M., & Amidou, S. (2018). Green synthesis of Ag/MgO nanoparticle modified nanohydroxyapatite and its potential for defluoridation and pathogen removal in groundwater. Physics and Chemistry of the Earth, Parts A/B/C, 107, 25–37. Azizi, N., Jazebizadeh, M. H., Azizi, F., Jahanmahin, O., Parsamehr, P. S., & Arzani, M. (2023). Enhancing CO2 permeation features of PEBAX-based membrane via incorporating MgO nanoparticles in its polymeric matrix. Materials Today Communications, 20, 105460. Banerjee, K., Das, S., Choudhury, P., Ghosh, S., Baral, R., & Choudhuri, S. K. (2017). A novel approach of synthesizing and evaluating the anticancer potential of silver oxide nanoparticles in vitro. Chemotherapy, 62, 279–289. Barbui, T., Vannucchi, A.  M., Alvarez-Larran, A., Iurlo, A., Masciulli, A., Carobbio, A., et  al. (2021). High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib. Leukemia, 35, 485–493. Becker, J., Raghupathi, K. R., St. Pierre, J., Zhao, D., & Koodali, R. T. (2011). Tuning of the crystallite and particle sizes of ZnO nanocrystalline materials in solvothermal synthesis and their photocatalytic activity for dye degradation. The Journal of Physical Chemistry C, 115(28), 13844–13850. Bloom, D.  E., & Cadarette, D. (2019). Infectious disease threats in the twenty-first century: Strengthening the global response. Frontiers in Immunology, 10, 549. Brandao, K., Deason-Towne, F., Perraud, A.  L., & Schmitz, C. (2013). The role of Mg2+ in immune cells. Immunologic Research, 55, 261–269. Calder, P. C., Carr, A. C., Gombart, A. F., & Eggersdorfer, M. (2020). Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients, 12. https://doi.org/10.3390/nu12041181 Camtakan, Z., Erenturk, S. A., & Yusan, S. D. (2012). Magnesium oxide nanoparticles: Preparation, characterization, and uranium sorption properties. Environmental Progress & Sustainable Energy, 31, 536. Caspi, R., Billington, R., Keseler, I.  M., Kothari, A., Krummenacker, M., Midford, P.  E., Ong, W.  K., Paley, S., Subhraveti, P., & Karp, P.  D. (2020). The MetaCyc database of metabolic pathways and enzymes—A 2019 update. Nucleic Acids Research, 48, D445–D453. Chaicherd, S., Killingsworth, M.  C., & Pissuwan, D. (2019). Toxicity of gold nanoparticles in a commercial dietary supplement drink on connective tissue fibroblast cells. SN Applied Sciences, 1, 1–8. Chellamuthu, P., Tran, F., Silva, K.  P. T., Chavez, M.  S., El-Naggar, M.  Y., & Boedicker, J.  Q. (2018). Engineering bacteria for biogenic synthesis of chalcogenide nanomaterials. Microbial Biotechnology, 12, 161–172. COVID-19 Map. Available online: https://coronavirus.jhu.edu/map.html. Accessed on 28 May 2023

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

221

de Jesus, J. R., Galazzi, R. M., Lopes Júnior, C. A., & Arruda, M. A. Z. (2022). Trace element homeostasis in the neurological system after SARS-CoV-2 infection: Insight into potential biochemical mechanisms. Journal of Trace Elements in Medicine and Biology, 71, 126964. De, M., Ghosh, P. S., & Rotello, V. M. (2008). Applications of nanoparticles in biology. Advanced Materials, 20, 4225–4241. Ding, Y., Zhang, G., Wu, H., Hai, B., Wang, L., & Qian, Y. (2001). Nanoscale magnesium hydroxide and magnesium oxide powders: Control over size, shape, and structure via hydrothermal synthesis. Chemistry of Materials, 13, 435–440. Dominguez, L. J., Veronese, N., Guerrero-Romero, F., & Barbagallo, M. (2021). Magnesium in infectious diseases in older people. Nutrients, 13, 180. Ebrahimi, M., Manafi, S., & Sharifianjazi, F. (2023). The effect of Ag2O and MgO dopants on the bioactivity, biocompatibility, and antibacterial properties of 58S bioactive glass synthesized by the sol-gel method. Journal of Non-Crystalline Solids, 15(606), 122189. Elsaesser, A., & Vyvyan Howard, C. (2012). Toxicology of nanoparticles. Advanced Drug Delivery Reviews, 64(2), 129–137. Fanni, D., Gerosa, C., Nurchi, V. M., Manchia, M., Saba, L., Coghe, F., Crisponi, G., Gibo, Y., Van Eyken, P., Fanos, V., et al. (2021). The role of magnesium in pregnancy and in fetal programming of adult diseases. Biological Trace Element Research, 199, 3647–3657. Farah, F.  H., & Farah, F.  H. (2019). Nanocarriers as delivery systems for therapeutics agents. International Journal of Pharmaceutical Sciences and Research, 10, 3487–3507. Farani, M. R., Khiarak, B. N., Tao, R., Wang, Z., Ahmadi, S., Hassanpour, M., Rabiee, M., Saeb, M. R., Lima, E. C., & Rabiee, N. (2022). 2D MXene nanocomposites: Electrochemical and biomedical applications. Environmental Science. Nano, 9, 4038–4068. Feeney, K. A., Hansen, L. L., Putker, M., Olivares-Yañez, C., Day, J., Eades, L. J., Larrondo, L. F., Hoyle, N. P., O’Neill, J. S., & van Ooijen, G. (2016). Daily magnesium fluxes regulate cellular timekeeping and energy balance. Nature, 532, 375–379. Fernandes, M., Singh, R. B., & K, Sarkar T, Singh P, Pratap Singh R. (2020). Recent applications of magnesium oxide (MgO) nanoparticles in various domains. Advanced Materials Letters, 11(8), 1–10. Fiorentini, D., Cappadone, C., Farruggia, G., & Prata, C. (2021). Magnesium: Biochemistry, nutrition, detection, and social impact of diseases linked to its deficiency. Nutrients, 13, 1136. Fouda, A., Hassan, S. E.-D., Saied, E., & Azab, M. S. (2020). An eco-friendly approach to textile and tannery wastewater treatment using maghemite nanoparticles (-Fe2O3-NPs) fabricated by Penicillium expansum strain (K-w). Journal of Environmental Chemical Engineering, 9, 104693. Ganapathi Rao, K., Ashok, C., Venkateswara Rao, K., & Shilpa Chakra, C. (2014). International Journal of Science and Research, 3, 43. García-Rodríguez, A., Stillwell, A. A., Tochilovsky, B. V., Tanzman, J. V., Limage, R., Kolba, N., Tako, E., Marques, C. N., & Mahler, G. J. (2022). The mechanistic effects of human digestion on magnesium oxide nanoparticles: implications for probiotics Lacticaseibacillus rhamnosus GG and Bifidobacterium bifidum VPI 1124. Environmental Science: Nano, 9(12), 4540–4557. Gelli, K., Porika, M., & Anreddy, R.  N. (2015). Assessment of pulmonary toxicity of MgO nanoparticles in rats. Environmental Toxicology, 30(3), 308–314. Gerloff, K., Albrecht, C., Boots, A. W., Förster, I., & Schins, R. P. (2009). Cytotoxicity and oxidative DNA damage by nanoparticles in human intestinal Caco-2 cells. Nanotoxicology, 3(4), 355–364. Giraud-Gatineau, A., Colson, P., Jimeno, M.-T., Zandotti, C., Ninove, L., Boschi, C., Lagier, J.-C., La Scola, B., Chaudet, H., & Raoult, D. (2020). Comparison of mortality associated with respiratory viral infections between December 2019 and March 2020 with that of the previous year in Southeastern France. International Journal of Infectious Diseases, 96, 154–156. Gomez-Romero, P. (2001). Hybrid organic–inorganic materials—in search of synergic activity. Advanced Materials, 13, 163–174. Goodarzi, F., Kock, M., Mielby, J., & Kegnæs, S. (2023). CO2 methanation using metals nanoparticles supported on high surface area MgO. Journal of CO2 Utilization, 69, 102396.

222

N. Sisubalan et al.

Gracias, D. H., Tien, J., Breen, T. L., Hsu, C., & Whitesides, G. M. (2009). Forming electrical networks in three dimensions by self-assembly. Science, 80, 1170–1172. Guerrero-Romero, F., Micke, O., Simental-Mendía, L.  E., Rodríguez-Morán, M., Vormann, J., Iotti, S., Banjanin, N., Rosanoff, A., Baniasadi, S., Pourdowlat, G., & Nechifor, M. (2023). Importance of magnesium status in COVID-19. Biology, 12(5), 735. Gurunathan, S., Qasim, M., Choi, Y., Do, J.  T., Park, C., Hong, K., Kim, J.-H., & Song, H. (2020). Antiviral potential of nanoparticles—Can nanoparticles fight against coronaviruses? Nanomaterials, 10, 1645. Heiligtag, F.  J., & Niederberger, M. (2013). The fascinating world of nanoparticle research. Materials Today, 16, 262–271. Hornak, J., Trnka, P., Kadlec, P., Michal, O., Mentlík, V., Šutta, P., Csányi, G.  M., & Tamus, Z. (2018). Magnesium oxide nanoparticles: Dielectric properties, surface functionalization and improvement of epoxy-based composites insulating properties. Nanomaterials, 8, 381. Huang, J., Liang, G., Lu, G., & Zhang, J. (2018). Conservation of acidic papers using a dispersion of oleic acid-modified MgO nanoparticles in a non-polar solvent. Journal of Cultural Heritage, 34, 61–68. Iotti, S., Frassineti, C., Sabatini, A., Vacca, A., & Barbiroli, B. (2005). Quantitative mathematical expressions for accurate in vivo assessment of cytosolic [ADP] and DeltaG of ATP hydrolysis in the human brain and skeletal muscle. Biochimica et Biophysica Acta, 1708, 164–177. Itatani, K., Tsujimoto, T., & Kishimoto, A. (2006). Thermal and optical properties of transparent magnesium oxide ceramics fabricated by post hot-isostatic pressing. Journal of the European Ceramic Society, 26, 639–645. Javed, A., Fatima, B., Hussain, D., Jawad, S.  E. Z., Subhan, M., & Najam-ul-Haq, M. (2023). Effect of Narcotic Drugs on Neurotransmitter: Electrochemical Determination of Heroin and Dopamine by Graphene Oxide/Carboxymethylcellulose/Magnesium Oxide Nanohybrid Membrane. Journal of Molecular Liquids, 122154. Jamkhande, P. G., Ghule, N. W., Bamer, A. H., & Kalaskar, M. G. (2019). Metal nanoparticles synthesis: an overview on methods of preparation, advantages and disadvantages, and applications. Journal of Drug Delivery Science and Technology, 53, 101174. https://doi.org/10.1016/j. jddst.2019.101174 Jayapriya, M., Premkumar, K., Arulmozhi, M., & Karthikeyan, K. (2020). One-step biological synthesis of cauliflower-like Ag/MgO nanocomposite with antibacterial, anticancer, and catalytic activity towards anthropogenic pollutants. Research on Chemical Intermediates, 46(3), 1771–1788. Jeevanandam, J., Chan, Y. S., & Danquah, M. K. (2016). Biosynthesis of metal and metal oxide nanoparticles. ChemBioEng Reviews, 3, 55–67. Karthikeyan, C., Sisubalan, N., Sridevi, M., Varaprasad, K., Basha, M. H., Shucai, W., & Sadiku, R. (2021). Biocidal chitosan-magnesium oxide nanoparticles via a green precipitation process. Journal of Hazardous Materials, 411, 124884. Karthikeyan, C., Sisubalan, N., Varaprasad, K., Aepuru, R., Yallapu, M. M., Viswanathan, M. R., & Sadiku, R. (2022). Hybrid nanoparticles from chitosan and nickel for enhanced biocidal activities. New Journal of Chemistry, 46(27), 13240–13248. Khalil, K. D., Bashal, A. H., Khalafalla, M., & Zaki, A. A. (2020). Synthesis, structural, dielectric and optical properties of chitosan-MgO nanocomposite. Journal of Taibah University for Science, 14, 975–983. Khan, F., Shahid, A., Zhu, H., Wang, N., Javed, M. R., Ahmad, N., Xu, J., Alam, M., & Mehmood, M.  A. (2022). Prospects of algae-based green synthesis of nanoparticles for environmental applications. Chemosphere, 293, 133571. Khan, M. I., Akhtar, M. N., Ashraf, N., Najeeb, J., Munir, H., Awan, T. I., Tahir, M. B., & Kabli, M. R. (2020). Green synthesis of magnesium oxide nanoparticles using Dalbergia sissoo extract for photocatalytic activity and antibacterial efficacy. Applied Nanoscience, 10, 2351–2364. Khoshnevisan, K., Maleki, H., Honarvarfard, E., Baharifar, H., Gholami, M., Faridbod, F., Larijani, B., Faridi Majidi, R., & Khorramizadeh, M. R. (2019). Nanomaterial based electrochemical sensing of the biomarker serotonin: a comprehensive review. Microchimica Acta, 186, 1–21. Khot, L. R., Sankaran, S., Maja, J. M., Ehsani, R., & Schuster, E. W. (2012). Crop Protection, 35, 64.

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

223

Kipcak, A. S., Acarali, N. B., Derun, E. M., Tugrul, N., & Piskin, S. (2014). Effect of magnesium borates on the fire-retarding properties of zinc borates. Journal of Chemistry, 2014, 512164. Klepser, M.  E. (2014). Socioeconomic impact of seasonal (epidemic) influenza and the role of over-the-counter medicines. Drugs, 74, 1467–1479. Konrad, M., Schlingmann, K.  P., & Gudermann, T. (2004). Insights into the molecular nature of magnesium homeostasis. American Journal of Physiology  – Renal Physiology, 286, F599–F605. Krishnamoorthy, K., Manivannan, G., Kim, S. J., Jeyasubramanian, K., & Premanathan, M. (2012). Antibacterial activity of MgO nanoparticles based on lipid peroxidation by oxygen vacancy. Journal of Nanoparticle Research, 14, 1–10. Kubota, T., Shindo, Y., Tokuno, K., Komatsu, H., Ogawa, H., Kudo, S., Kitamura, Y., Suzuki, K., & Oka, K. (2005). Mitochondria are intracellular magnesium stores: Investigation by simultaneous fluorescent imagings in PC12 cells. Biochimica et Biophysica Acta, 1744, 19–28. Kumar, S., Kumar, B., Sehgal, R., Wani, M. F., Kumar, D., Sharma, M. D., Singh, V., Sehgal, R., & Kumar, V. (2023). Advantages and disadvantages of metal nanoparticles. In Nanoparticles reinforced metal nanocomposites: Mechanical performance and durability (pp.  209–235). Springer Nature Singapore. Kumar, A., & Kumar, J. (2008). On the synthesis and optical absorption studies of nano-size magnesium oxide powder. Journal of Physics and Chemistry of Solids, 69, 2764–2772. Li, F. Y., Chaigne-Delalande, B., Kanellopoulou, C., Davis, J. C., Matthews, H. F., Douek, D. C., Cohen, J. I., Uzel, G., Su, H. C., & Lenardo, M. J. (2011). Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature, 475, 471–476. Liang, C., Sasaki, T., Shimizu, Y., & Koshizaki, N. (2004). Chemical Physics Letters, 389, 58. Mahmoud, A., Ezgi, Ö., Merve, A., & Özhan, G. (2016). In vitro toxicological assessment of magnesium oxide nanoparticle exposure in several mammalian cell types. International Journal of Toxicology, 35(4), 429–437. Mammoli, F., Castiglioni, S., Parenti, S., Cappadone, C., Farruggia, G., Iotti, S., Davalli, P., Maier, J. A. M., Grande, A., & Frassineti, C. (2019). Magnesium is a key regulator of the balance between osteoclast and osteoblast differentiation in the presence of vitamin D3. International Journal of Molecular Sciences, 20, 385. Medhi, R., Srinoi, P., Ngo, N., Tran, H.-V., & Lee, T. R. (2020). Nanoparticle-based strategies to combat COVID-19. ACS Applied Nano Materials, 3, 8557–8580. Meng, X., Zare, I., Yan, X., & Fan, K. (2020). Protein-protected metal nanoclusters: An emerging ultra-small nanozyme. Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology, 12, e1602. Moura, D., Souza, M.  T., Liverani, L., Rella, G., Luz, G.  M., Mano, J.  F., & Boccaccini, A. R. (2017). Development of a bioactive glass-polymer composite for wound healing applications. Materials Science and Engineering: C, 76, 224–232. Mughal, B., Zaidi, S. Z., Zhang, X., & Hassan, S. U. (2021). Biogenic nanoparticles: Synthesis, characterisation and applications. Applied Sciences, 11(6), 2598. Nandhini, S. N., Sisubalan, N., Vijayan, A., Karthikeyan, C., Gnanaraj, M., Gideon, D. A., Jebastin, T., Varaprasad, K., & Sadiku, R. (2023 Jan). Recent advances in green synthesized nanoparticles for bactericidal and wound healing applications. Heliyon, 21, e13128. Narayanan, R., & El-Sayed, M. A. (2004). Shape-dependent catalytic activity of platinum nanoparticles in colloidal solution. Nano Letters, 4, 1343–1348. Naz, S., Gul, A., & Zia, M. (2020). Toxicity of copper oxide nanoparticles: a review study. IET Nanobiotechnology, 14, 1–13. Nejati, M., Rostami, M., Mirzaei, H., Rahimi-Nasrabadi, M., Vosoughifar, M., Nasab, A. S., & Ganjali, M.  R. (2021). Green methods for the preparation of MgO nanomaterials and their drug delivery, anti-cancer and anti-bacterial potentials: A review. Inorganic Chemistry Communications, 136, 109107.

224

N. Sisubalan et al.

Nguyen, N. T., Nguyen, L. M., Nguyen, T. T., Tran, U. P., Nguyen, D. T., & Van Tran, T. (2023). A critical review on the bio-mediated green synthesis and multiple applications of magnesium oxide nanoparticles. Chemosphere, 312, 137301. Noori, A. J., & Kareem, F. A. (2019). The effect of magnesium oxide nanoparticles on the antibacterial and antibiofilm properties of glass-ionomer cement. Heliyon, 5(10), e02568. Ouraipryvan, P., Sreethawong, T., & Chavadej, S. (2009). Synthesis crystalline MgO nanoparticle with mesoporous-assembled structure via a surfactant-modified sol-gel process. Materials Letters, 63, 1862–1865. Panchal, P., Paul, D.  R., Gautam, S., Meena, P., Nehra, S., Maken, S., & Sharma, A. (2022). Photocatalytic and antibacterial activities of green synthesized Ag doped MgO nanocomposites towards environmental sustainability. Chemosphere, 297, 134182. Park, J.  Y., Lee, Y.  J., Jun, K.  W., Baeg, J.  O., & Yim, D.  J. (2006). Journal of Industrial and Engineering Chemistry, 12, 882. Passamonti, F., Cattaneo, C., Arcaini, L., Bruna, R., Cavo, M., Merli, F., et al. (2020). Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol, 7, e737–e745. Pilarska, A. A., Klapiszewski, Ł., & Jesionowski, T. (2017). Recent development in the synthesis, modification and application of Mg(OH)2 and MgO: A review. Powder Technology, 319, 373–407. Prasanth, R., Kumar, S.  D., Jayalakshmi, A., Singaravelu, G., Govindaraju, K., & Kumar, V. G. (2019). Green synthesis of magnesium oxide nanoparticles and their antibacterial activity. Indian Journal of Geo Marine Sciences, 48, 1210–1215. Rajendran, V., Deepa, B., & Mekala, R. (2018). Studies on structural, morphological, optical and antibacterial activity of Pure and Cu-doped MgO nanoparticles synthesized by co-precipitation method. Materials Today Proceedings, 5(2), 8796–8803. Ramezani Farani, M., Farsadrooh, M., Zare, I., Gholami, A., & Akhavan, O. (2023). Green synthesis of magnesium oxide nanoparticles and nanocomposites for photocatalytic antimicrobial, antibiofilm and antifungal applications. Catalysts, 13(4), 642. Raveesha, H., Nayana, S., Vasudha, D., Begum, J. S., Pratibha, S., Ravikumara, C., & Dhananjaya, N. (2019). The electrochemical behavior, antifungal and cytotoxic activities of phytofabricated MgO nanoparticles using Withania somnifera leaf extract. Journal of Science: Advanced Materials and Devices, 4(1), 57–65. Ray, P. C., Yu, H., & Fu, P. P. (2009). Toxicity and environmental risks of nanomaterials: Challenges and future needs. Journal of Environmental Science and Health, Part C, 27, 1–35. Renero-Lecuna, C., Iturrioz-Rodríguez, N., González-Lavado, E., Padín-González, E., Navarro-­ Palomares, E., Valdivia-Fernández, L., García-Hevia, L., Fanarraga, M.  L., & González-­ Legarreta, L. (2019). Effect of size, shape, and composition on the interaction of different nanomaterials with HeLa cells. Journal of Nanomaterials, 2019. Roy, S., Sadhukhan, R., Ghosh, U., & Das, T.  K. (2015). Interaction studies between biosynthesized silver nanoparticle with calf thymus DNA and cytotoxicity of silver nanoparticles. Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy, 141, 176–184. Rubin, H. (2005). Magnesium: The missing element in molecular views of cell proliferation control. Bioessays, 27, 311–320. Sain, M., Park, S., Suhara, F., & Law, S. (2004). Flame retardant and mechanical properties of natural fibre–PP composites containing magnesium hydroxide. Polymer Degradation and Stability, 83, 363–367. Sargenti, A., Castiglioni, S., Olivi, E., Bianchi, F., Cazzaniga, A., Farruggia, G., Cappadone, C., Merolle, L., Malucelli, E., Ventura, C., et al. (2018). Magnesium deprivation potentiates human mesenchymal stem cell transcriptional remodeling. International Journal of Molecular Sciences, 19, 1410.

Eco-Friendly Synthesis of MgO Nanoparticles for Biomedical Applications: Advances…

225

Sawai, J., Kojima, H., Igarashi, H., Hashimoto, A., Shoji, S., Sawaki, T., et al. (2000). Antibacterial characteristics of magnesium oxide powder. World Journal of Microbiology and Biotechnology, 16(2), 187–194. Sawai, J., Kojima, H., Ishizu, N., Itoh, M., Igarashi, H., Sawaki, T., & Shimizu, M. (1997). Bactericidal action of magnesium oxide powder. Journal of Inorganic Biochemistry, 67(1-4), 443–443. Schuchardt, J. P., & Hahn, A. (2017). Intestinal absorption and factors influencing bioavailability of magnesium—An update. Current Nutrition & Food Science, 13, 260–278. Shaikh, S. F., Mane, R. S., Min, B. K., Hwang, Y. J., & Joo, O. (2016). D-sorbitol-induced phase control of TiO2 nanoparticles and its application for dye-sensitized solar cells. Scientific Reports, 6, 1–10. Shanmugam, J., Sharmili Sundararaj, A., Shanmugasundaram, R., Ravichandran, B., Mani, M., Mohammed Riyaz, S. U., Dhayalan, M., Cid-Samamed, A., & Simal-Gandara, J. (2023). Green preparation of bract extract (Musa acuminate) doped magnesium oxide nanoparticles and their bioefficacy. Applied Organometallic Chemistry, 37(5), e7063. Shen, Y., He, L., Yang, Z., & Xiong, Y. (2020). Corrosion behavior of different coatings prepared on the surface of AZ80 magnesium alloy in simulated body fluid. Journal of Materials Engineering and Performance, 29, 1609–1621. Singh, H.  L., Chahar, M., Sahal, S., & Khaturia, S. (2023). Sustainable synthesis of benzopyran derivatives catalyzed by MgO nanoparticles: Spectral, DFT and TEM analysis. Results in Chemistry, 5, 100884. Singh, R.  P. (2017). Application of nanomaterials towards development of nanobiosensors and their utility in agriculture. In R. Prasad, K. Manoj, & V. Kumar (Eds.), Nanotechnology: An agricultural paradigm (pp. 293–303). Springer. Singh, R.  P. (2019). Utility of nanomaterials in food safety. In Food safety and human health (pp. 285–318). Elsevier. Sisubalan, N., Karthikeyan, C., Kumar, V. S., Varaprasad, K., Vanajothi, R., & Sadiku, R. (2021). Biocidal activity of Ba 2+-doped CeO 2 NPs against Streptococcus mutans and Staphylococcus aureus bacterial strains. RSC Advances, 11(49), 30623–30634. Sisubalan, N., Ramkumar, V. S., Pugazhendhi, A., Karthikeyan, C., Indira, K., Gopinath, K., & Basha, M.  H. G. (2018). ROS-mediated cytotoxic activity of ZnO and CeO2 nanoparticles ­synthesized using the Rubia cordifolia L. leaf extract on MG-63 human osteosarcoma cell lines. Environmental Science and Pollution Research, 25(11), 10482–10492. Sohrabi, L., & Taleshi, F. (2014). Effect of carbon nanotubes support on band gap energy of MgO nanoparticles. Journal of Materials Science: Materials in Electronics, 25, 4110–4114. Spagnoli, D., Allen, J.  P., & Parker, S.  C. (2011). The structure and dynamics of hydrated and hydroxylated magnesium oxide nanoparticles. Langmuir, 27, 1821–1829. Štengl, V., Bakardjieva, S., Maříková, M., Bezdička, P., & Šubrt, J. (2003). Materials Letters, 57, 3998. Subash, M., Chandrasekar, M., Panimalar, S., Inmozhi, C., Parasuraman, K., Uthrakumar, R., & Kaviyarasu, K. (2023 Feb). Pseudo-first kinetics model of copper doping on the structural, magnetic, and photocatalytic activity of magnesium oxide nanoparticles for energy application. Biomass Conversion and Biorefinery, 13(4), 3427–3437. Sukhanova, A., Bozrova, S., Sokolov, P., Berestovoy, M., Karaulov, A., & Nabiev, I. (2018). Dependence of nanoparticle toxicity on their physical and chemical properties. Nanoscale Research Letters, 13, 44. Tang, C. F., Ding, H., Jiao, R. Q., Wu, X. X., & Kong, L. D. (2020 Nov). Possibility of magnesium supplementation for supportive treatment in patients with COVID-19. European Journal of Pharmacology, 5(886), 173546. Tang, H., Zhou, X.-B., & Liu, X.-L. (2013). Effect of magnesium hydroxide on the flame retardant properties of unsaturated polyester resin. Procedia Engineering, 52, 336–341.

226

N. Sisubalan et al.

Tian, Q., Ye, J., Yuan, W., Zhang, S., Shi, L., Zhong, J., & Ning, G. (2020). Highly effective antibacterial activity of lithium-doped magnesium oxide particles synthesized by the microwave-­ assisted hydrothermal route. Powder Technology, 371, 130–141. Troeger, C., Forouzanfar, M., Rao, P. C., Khalil, I., Brown, A., Swartz, S., Fullman, N., Mosser, J., Thompson, R. L., Reiner, R. C., et al. (2017). Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: A systematic analysis for the global burden of disease study 2015. The Lancet Infectious Diseases, 17, 1133–1161. Verma, S. K., Das, A. K., Patel, M. K., Shah, A., Kumar, V., & Gantait, S. (2018). Engineered nanomaterials for plant growth and development: a perspective analysis. Science of The Total Environment, 630, 1413–1435. https://doi.org/10.1016/j.scitotenv.2018.02.313 Wallace, T. C. (2020). Combating COVID-19 and building immune resilience: A potential role for magnesium nutrition? Journal of the American College of Nutrition, 39, 685–693. https://doi. org/10.1080/07315724.2020.1785971 Wang, W.-N., Tarafdar, J.  C., & Biswas, P. (2013). Nanoparticle synthesis and delivery by an aerosol route for watermelon plant foliar uptake. Journal of Nanoparticle Research, 15, 1417. https://doi.org/10.1007/s11051-­013-­1417-­8 Wang, Z. L., Zhang, X., Fan, G. J., Que, Y., Xue, F., & Liu, Y. H. (2022). Toxicity effects and mechanisms of MgO nanoparticles on the oomycete pathogen phytophthora infestans and its host Solanum tuberosum. Toxics, 10(10), 553. Wang, B., Xiong, X., Ren, H., & Huang, Z. (2017). Preparation of MgO nanocrystals and catalytic mechanism on phenol ozonation. RSC Advances, 7, 43464–43473. Yaqoob, A. A., Parveen, T., Umar, K., & Mohamad Ibrahim, M. N. (2020). Role of nanomaterials in the treatment of wastewater: A review. Water, 12, 495. Yu, J. C., Xu, A., Zhang, L., Song, R., & Wu, L. (2004). The Journal of Physical Chemistry B, 108, 64. Zhang, X., Wang, W., Zhang, Y., Zeng, T., Jia, C., & Chang, L. (2018). Loading Cu-doped magnesium oxide onto surface of magnetic nanoparticles to prepare magnetic disinfectant with enhanced antibacterial activity. Colloids and Surfaces B: Biointerfaces, 161, 433–441. Zhao, L. C., Cui, C. X., Liu, S. J., & Qi, Y. M. (2009). Influence of in situ MgO coating on corrosion resistance of pure magnesium in normal saline. Advances in Materials Research, 79–82, 1039–1042. Zhou, J., Yang, S., & Yu, J. (2011). Facile fabrication of mesoporous MgO microspheres and their enhanced adsorption performance for phosphate from aqueous solutions. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 379, 102–108. Zhu, X., Vo, C., Taylor, M., & Smith, B.  R. (2019). Non-spherical micro-and nanoparticles in nanomedicine. Materials Horizons, 6, 1094–1121. Zhu, X., Wu, D., Wang, W., Tan, F., Wong, P. K., Wang, X., et al. (2016). Highly effective antibacterial activity and synergistic effect of Ag-MgO nanocomposite against Escherichia coli. Journal of Alloys and Compounds, 684, 282–290.

Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral, and Anticancer Therapies Karthikeyan Chandrasekaran, Varaprasad Kokkarachedu, Natarajan Sisubalan, Arumugam Vijayan, P. Hendry Moses, P. Edison Raj Godwin, C. Kelvin Adaikalam, S. Gowri, J. Jason Mathews, A. S. Haja Hameed, and J. Ebenezar

Overview Nanotechnology has emerged as a significant research field due to its high surface-­ to-­volume ratio and small size, which can result in enhanced electrical, optical, magnetic, catalytic, and antibacterial properties (Gebreslassie & Gebretnsae, 2021). Tin oxide (SnO2) nanoparticles are important n-type metal oxide semiconductors among the various nanomaterials. SnO2 nanoparticles possess a tetragonal rutile structure with lattice constants a = b = 0.473 nm and c = 0.318 nm, and they exhibit

K. Chandrasekaran KIRND Institute of Research and Development PVT LTD, Tiruchirappalli, Tamil Nadu, India V. Kokkarachedu (*) Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile e-mail: [email protected] N. Sisubalan · P. Edison Raj Godwin · J. Jason Mathews Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand A. Vijayan Department of Microbiology, SRM Institute of Science and Technology, Tiruchirappalli Campus, Tiruchirappalli, Tamil Nadu, India P. Hendry Moses · A. S. Haja Hameed · J. Ebenezar Jamal Mohamed College, Autonomous (Affiliated to Bharathidasan University), Tiruchirappalli, Tamil Nadu, India C. Kelvin Adaikalam · S. Gowri Cauvery College for women, Autonomous (Affiliated to Bharathidasan University), Tiruchirappalli, Tamil Nadu, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_10

227

228

K. Chandrasekaran et al.

a bulk band gap of 3.6–3.8 eV at room temperature (Meena Kumari & Philip, 2015). The therapeutic characteristics of SnO2 nanoparticles include biocompatibility, antioxidant, antibacterial, antifungal, and anticancer activities (Meena Kumari & Philip, 2015; Roopan et al., 2015). SnO2 nanoparticles exist in different oxygen stoichiometric compositions, including the n-type SnO2 and the p-type Sn3O4 (Huang et  al., 2022). The phase transitions of SnO2 are particularly intriguing. Under high-pressure conditions, SnO2 undergoes phase transitions from rutile type (P42/mnm) to CaCl2 type (Pnnm), α-PbO2 type (Pbcn), pyrite type (Pa3 ̅), ZrO2 type (Pbca), fluorite type (Fm3 ̅m), and cotunnite type (Pnam) (Huang et al., 2022). The properties of SnO2 nanoparticles differ significantly from those of their bulk counterparts due to quantum confinement, mainly when their size is smaller than or comparable to their exciton Bohr radius. These variations in physical properties make SnO2 a promising candidate for a wide range of applications, such as optoelectronics, sensing, lasers, and solar cells (Ahmed et al., 2012; Meena Kumari & Philip, 2015). Medical investigations have shown that surface modification of SnO2 nanoparticles (achieving large surface area and grain size while maintaining a small particle size) can improve their efficiency and efficacy. This surface alteration can be achieved through nanoscale doping with transition metals such as Mn, Fe, Cr, Cu, and Co, as well as with biomolecules. SnO2 doped with transition metals and biomolecules can be utilized as antimicrobials, anticancer agents, antitumor agents, biosensors, antioxidants, bioimaging agents, and drug delivery agents (Gu et  al., 2003; Shahid et  al., 2017). Currently, significant research is being conducted to develop various SnO2 nanostructures, including nanoparticles, nanowires, nanorods, nanosheets, nanospheres, and nanotubes, using chemical and physical methods such as sol-gel, laser ablation, hydrothermal, ultrasonics, high-energy ball milling, and green methods (Dheyab et al., 2022; Meena Kumari & Philip, 2015) (Figs. 1 and 2).

Advantages and Disadvantages Advantages 1. Nanostructures of SnO2 depend mostly on their morphologies and structural properties. Therefore, with considerable effort, the preferred modification is possible (Zhao et al., 2015). 2. SnO2 is advantageous for use in perovskite solar cells because of its high mobility, large optical band gap, deep conduction band, and valance band (Xiong et al., 2018). 3. Due to the quantum size effect, SnO2 NPs with dimensions less than 10 nm possess unique and enhanced chemical, physical, and biomedical properties (Chen et al., 2018).

Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral…

229

Fig. 1 SnO2 tetragonal rutile structure. The orange sphere depicts tin, and the blue sphere depicts oxygen. (Image source: Pinto et al., 2022)

Fig. 2 SnO2 crystal structures. (a) Rutile (P42/mnm) and CaCl2 type (Pnnm), (b) α-PbO2 type (Pbcn), (c) pyrite type (Pa 3 ), (d) ZrO2 type (Pbca), (e) fluorite type (Fm 3 m), and (f) cotunnite type (Pnam). (Image source: Das & Jayaraman, 2014)

230

K. Chandrasekaran et al.

4. It possesses high thermal stability, good electrical conductivity, and enhanced optical characteristics (Zuorro et al., 2022). 5. SnO2 has a strong oxidizing potential, chemical stability, corrosion resistance, and low toxicity (Zuorro et al., 2022).

Disadvantages 1. High resistivity and crystal structure deficiency due to ion exchange affect the electrochemical properties of SnO2 (Sharma et al., 2021). 2. High power consumption needed to maintain the optimum operating temperature hinders SnO2 gas censor application (Yan et al., 2019). 3. Potential toxicity due to their small size and high reactivity (Chávez-Calderón et al., 2016). In addition, agglomeration of SiO2, which can reduce their stability and activity.

Toxicity Effect (A Mechanism) on Living Cells In this chapter, we will examine the cytotoxic effects of SnO2 on living cells. When an external toxicant has the potential to destroy cells and significantly impair organ function, it is referred to as a cell toxin. Chemical agents, environmental pollutants, plant extracts, and synthetic pharmaceuticals all have the potential to be harmful to cells. Mechanisms of cell toxicity have been investigated for decades, and they continue to spark the interest of scientists today. Numerous distinct processes contribute to the toxicity of cells. Overproduction of nitric oxide (NO), reactive oxygen species (ROS), and the accompanying oxidative stress have been recognized for a long time as a potential consequence of toxicant exposure. Toxins can also directly harm cells through a process known as apoptosis and cause DNA damage. Oxygen nanoparticles (NP) offer enormous medical promise; yet, their cell toxicity is only slowly being explored. Nanoparticles ranging in size from 1 to 100 nm (nanometers) may be able to enter the cells of a human. This can lead to increased exposure at work and in the community, which is extremely detrimental to human health. When nanoparticles are introduced into human cells, they may trigger a chain reaction of harmful alterations (Zhang, 2018). The mechanism of cell toxicity is depicted in Fig. 3. SnO2 toxicity against bacterial strains are caused by the formation of ROS, including hydroxyl radical (OH−), superoxide anion (O2−), and singlet oxygen (1O2). ROS generation can damage the cell membrane, resulting in the modification of DNA, lipids, and cellular proteins leading to cell death. Henceforth, subsequent modification in the DNA of treated bacterial cells by SnO2 nanoparticles results in damage to the imitation ability of DNA.  As a result, the proteins and enzyme

Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral…

231

Fig. 3  Mechanism of cell toxicity mainly include the following: (a) NO or cytokine overproduction-­ induced oxidative burst, (b) ROS and oxidative stress, (c) DNA damage, and (d) mitochondrial dysfunction. Toxicant is shown as green. (Image source: Zhang, 2018)

expression that are vital for the production of adenosine triphosphate (ATP) become incapacitated (Khan et al., 2018). SnO2 nanoparticles were observed to exhibit cellular DNA condensation events that the leakage of the cytoplasmic component of the damaged microorganisms may accompany. The presence of micromolar amounts of Co+2 and Sn+4 in produced NAPs causes DNA impairment. Being intermediate and hard acids, Co+2 and Sn+4 have the propensity to react with intermediate and hard bases containing sulfur and phosphorus, for example, R-SH, R-S-R, and PR3. They can, therefore, selectively interact with sulfur-containing proteins and the phosphorous-containing DNA of the cell (Khan et al., 2018).

Antimicrobial Characteristics The prevalence of microorganisms that cause health hazards and environmental pollution is increasing; therefore, the need for innovative strategies and antimicrobial agents are crucial. The antimicrobial efficacy of nanoparticles are dependent on their ability to generate ROS, such as hydroxyl radicals (OH−), super anion (O2−), and singlet oxygen (1O2), as this is the main reason proposed for inducing cell membrane damage that results in the modification of DNA, lipids, and cellular proteins, ultimately leading to cell death (Khan et al., 2018). Metal oxide nanoparticles have

232

K. Chandrasekaran et al.

Fig. 4 SnO2 antibacterial mechanism. (Image source: Goyal et al., 2022)

a high surface area, improved chemical and biological activity, and the ability to rupture cell membranes (Vidhu & Philip, 2015). Among them, SnO2 nanoparticles are an attractive candidate for use in photocatalytic and biological applications due to their size and shape-dependent properties. It has been discovered that SnO2 nanoparticles are effective antimicrobial therapeutics for several strains (Goyal et al., 2022). Both gram-positive and gram-negative bacterial strains have negatively charged cell walls that aid the microbes by maintaining homeostasis and protecting them from environmental threats. SnO2 forms electrostatic interactions with the cell membrane and damages them by releasing Sn4+. Further, SnO2 nanoparticles penetrate the damaged cell membrane, break the phosphate and hydrogen bonds, and cause DNA damage, organ leakage, and microbe death (Goyal et al., 2022; Vidhu & Philip, 2015). Their antibacterial mechanism is depicted in Fig. 4.

Recent Studies on Antimicrobial Applications Metal oxide nanoparticles, including SnO2, have been reported to penetrate the protective coatings of bacteria. Among different semiconductor metal oxides like ZnO, TiO2, and SiO2, SnO2 stands out due to its wide bandgap energy and advanced photocatalytic activity. Specifically, n-type semiconducting SnO2 nanoparticles possess a wide bandgap energy of 3.6–3.8  eV (Bagheri-Mohagheghi et  al., 2008; Doyan et al., 2021). The size of nanoparticles are crucial to their behavior and biological interactions (Varaprasad et  al., 2022). For example, in biomedicine, nanoparticle size is critical in determining cellular uptake efficiency, biodistribution, and clearance from the body. Studies have shown that smaller nanoparticles are more readily internalized by cells than larger ones (Varaprasad et al., 2020). This is attributed to the larger surface area-to-volume ratio of smaller particles, making them more accessible to cellular receptors and uptake mechanisms. Additionally,

Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral…

233

nanoparticles’ shape and surface chemistry also influence their cellular uptake efficiency. Hence, size, shape, and surface chemistry are essential in nanoparticle design for biomedical applications. Optimizing these parameters enables the development of nanoparticles with improved cellular uptake efficiency, targeting specificity, and therapeutic efficacy.

Antimicrobial Activity Vidhu and Philip (2015) synthesized bioactive SnO2 nanoparticles using Saraca indica flower and tested their efficacy against Escherichia coli (E. coli) bacterial strains. Their investigation suggested that the enhanced antibacterial mechanism of SnO2 nanoparticle is due to the production of active oxygen species, which interact and penetrate the E. coli cell membrane, causing cell disruption (Vidhu & Philip, 2015). Fakhri et al. (2015) examined the antimicrobial activity of SnO2, SnS2, and SnO2/SnS2 nanostructures against bacterial strains E. coli and Staphylococcus (S. aureus) and the antifungal strain Candida albicans (C. albicans). The SnO2/SnS2 nanostructures exhibited enhanced antimicrobial activity, possibly due to a synergistic effect of the nanoparticles (Fakhri et al., 2015). Henry et al. (2015) investigated the efficacy of annealed SnO2 films against E. coli and Bacillus. They observed that bacterial growth was apparent on untreated surfaces but not on SnO2-coated surfaces. The development inhibition may be attributed to the formation of reactive oxygen species, electrostatic interaction with the bacterial cell wall, and photocatalytic properties (Henry et al., 2015). Al-Hada et al. (2018) studied the antimicrobial efficacy of SnO2 nanoparticles calcinated at different temperatures (bulk, 500 °C: 4 nm, 600 °C: 6.7 nm, 700 °C: 9.5 nm, 800 °C: 15.5 nm) against gram-negative (G-) E. coli and gram-positive (G+) Bacillus subtilis (Al-Hada et al., 2018). Their investigation suggested that the antibacterial efficacy increased as the nanoparticle size decreased. Evstropieva et  al. (2019) investigated the bactericidal effects of ZnO-­ SnO2 nanoparticle coatings on a glass surface using the polymer salt method against S. aureus and E. coli (Evstropiev et al., 2019). The addition of SnO2 to ZnO resulted in enhanced antibacterial activity. Furthermore, the results suggested that SnO2 decreased the size of ZnO and increased their surface area, which was the primary reason for the enhanced ZnO-SnO2 activity (Evstropiev et al., 2019). Mostafa and Mwafy (2020) synthesized SnO2/Au nanoalloys and examined their efficacy against E. coli and B. subtilis (Mostafa & Mwafy, 2020). Their research revealed that the synthesized nanoparticles were more effective against B. subtilis than E. coli. Furthermore, the accumulation of nanoparticles on bacterial strains induced distinct adsorption-desorption chemical-physical processes in each cytoplasmic lipid cell membrane, resulting in distinct membrane disruptions and cell death. Sathishkumar and Geethalakshmi (2020) synthesized pure and Cu-doped SnO2 nanoparticles using a microwave-assisted method and investigated their biocidal activity against S. aureus and Pseudomonas aeruginosa (P. aeruginosa). The biocidal activity of SnO2 nanoparticles increased with an increase in Cu concentration. In addition,

234

K. Chandrasekaran et al.

Fig. 5 (a) Clinical pathogens against standard SA, SnO2, SASnO2 NPs, and antibiotic amoxicillin treatment with S. aureus, S. pneumoniae. K. pneumonia, and E. coli bacterial strains. (b) Zone of inhibition of SA, SnO2, SASnO2 NPs, and antibiotic amoxicillin treated with gram-positive and gram-negative bacterial strains. (c) A schematic diagram of the mechanisms of SnO2 and SASnO2 NPs under visible light irradiation. (d) Control image E. coli. (e) E. coli treated with SASnO2 NPs, and (f) (i) control (ii) SnO2, (iii) SASnO2 NPs treated with E. coli for live/death cell assay, and (iv) cell viability graph. (Karthikeyan et al., 2023)

SnO2 nanoparticles released Cu2+ and Sn4+, which reacted with the carboxy groups of surface proteins on the cell wall, enhanced the generation of ROS, and affected the integrity of the cell membrane, causing damage to the cell wall (Sathishkumar & Geethalakshmi, 2020). Vijayalakshmi et al. (2020) investigated the antimicrobial activity of Ag@SnO2 core-shell nanoparticles against the antibacterial strains B. subtilis and Proteus mirabilis (P. mirabilis), as well as the antifungal strains C. albicans and Aspergillus niger (A. niger) (Vijayalakshmi et al., 2020). Their study found that SnO2 doped with Ag showed a more significant decrease in the microbial count. In addition, Ag penetrated the bacterial cells and destroyed them due to its oligodynamic effect. At the same time, the presence of SnO2 at the outer layer prevented the diffusion of Ag beyond the core, resulting in improved antifungal activity. Haq et al. (2022) synthesized SnO2 nanoparticles and investigated their antifungal activity against C. albicans and A. nigar (Haq et  al., 2022). Their results indicated that the antifungal activity was concentration-dependent, with increased activity observed with increasing nanoparticle concentration. This could be attributed to the increased number of particles in the solution, providing more binding sites for the fungi to interact with. Most antifungal agents operate non-specific, either altering the permeability of the cell wall or causing cytoplasmic fluid leakage, leading to the death of fungi [26]. Karthikeyan et  al. studied the antibacterial activity of sodium alginate-modified SnO2 surface matrix (SASnO2) and compared it to SnO2 nanoparticles (Karthikeyan et  al., 2023). The results showed that SASnO2 exhibited superior antibacterial

Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral…

235

activity, which was attributed to its ability to generate ROS and induce stronger photo-­oxidative stress, leading to bacterial cell death (Fig.  5). Cytotoxicity tests were performed using SASnO2 NPs against clinical pathogens including Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, and Escherichia coli. The bandgap behavior of the nanoparticles played a crucial role in ROS-mediated cell death. SASnO2 nanoparticles with a reduced particle size of 19 nm had a larger bandgap of 3.53 eV compared to SnO2 nanoparticles with a particle size of 38 nm (bandgap of 3.47 eV). This enhanced bandgap effect contributed to the improved antibacterial activity of SASnO2 nanoparticles. The study also provided equations describing the ROS production (OH, H2O2, and O2−) by SASnO2 nanoparticles.

Anticancer Properties Cancer, characterized by abnormal and uncontrolled cell growth, is a major global health challenge, ranking second to cardiovascular diseases (Huang et al., 2022). However, conventional cancer drugs often face limitations in terms of their ability to be effectively absorbed by cancer cells. This necessitates repeated administration, which can lead to high-dose toxicity. Using SnO2 nanoparticles (NPs) to address these challenges in cancer treatment shows promise. There are several potential applications and advantages of SnO2 NPs in cancer therapeutics. One approach to enhancing the properties of SnO2 NPs are through surface modification using polymer networks. This allows for optimizing NPs’ physicochemical characteristics, such as size, shape, and three-dimensional arrangement. Incorporating SnO2 NPs into single or multicomponent polymeric matrices can improve their photocatalytic and biocidal properties. Sodium alginate (SA), an anionic biopolymer, is a hydrophilic polysaccharide that is biocompatible, biodegradable, and non-toxic. In addition, SA contains carboxylate and hydroxyl functional groups, which play a vital role in forming hybridization networks. These networks enhance the surface properties of nanomaterials, making them more effective in cancer therapeutics (Karthikeyan et al., 2023). In a study conducted by Karthikeyan et  al. (2023), the anticancer efficacy of SnO2 and SASnO2 NPs was evaluated using MDA-MB-231 triple-negative breast cancer 3D tumor spheroids (Fig. 6) (Karthikeyan et al., 2023). The results demonstrated that both SnO2 and SASnO2 NPs significantly reduced the volume of the MDA-MB-231 tumor spheroid compared to the untreated control group. Interestingly, the 3D breast cancer tumor spheroids treated with SASnO2 NPs exhibited more significant shrinkage than those treated with SnO2 NPs, indicating that SASnO2 NPs possessed more potent cytotoxicity against 3D breast cancer cell spheroids. Live/dead assays were performed on the SnO2 and SASnO2 NP-treated spheroids, as depicted in Fig. 6. The control group showed no morphological changes and displayed green fluorescence, indicating 100% viability. In contrast, the spheroids

236

K. Chandrasekaran et al.

Fig. 6  Anticancer activity of SnO2 and SASnO2 NPs against MDA-MB-231 3D tumor spheroid models for 24, 48, and 72 h. (a) Macroscopic images of a spheroid and (b) change of spheroid volume (https://doi.org/10.1016/j.jiec.2023.04.001)

treated with SnO2 and SASnO2 NPs exhibited noticeable morphological changes. The SASnO2 NP-treated group showed higher red fluorescence intensity than the SnO2 NP-treated group. Upon merging both dyes, it was evident that SASnO2 NPs had a higher percentage of cell death (red solid intensity) than cell viability (weak green intensity). These findings highlight the potent anticancer activity of SASnO2 NPs against breast cancer 3D tumor spheroids, surpassing that of SnO2 NPs. The results also indicated that the nanoparticles’ size influenced tumor cells’ uptake rate. SASnO2 NPs, being smaller particles with a larger surface area (19 nm), exhibited higher uptake than SnO2 NPs, which had a larger particle size (38 nm). This size-dependent effect allowed SASnO2 NPs to have more contact with biological membranes, facilitating their internalization by cells and ultimately leading to enhanced anticancer activity (Fig. 7). Selva Bilge et  al. reported, “SnO2 nanoparticles/waste masks carbon hybrid materials for DNA biosensor application on voltammetric detection of anticancer drug pazopanib presents a novel biosensor for the detection of pazopanib, an anticancer drug, using SnO2 nanoparticles and waste masks carbon hybrid materials” (Bilge et  al., 2023). The researchers synthesized the SnO2 nanoparticles using a simple precipitation method and then mixed them with waste mask carbon, which is a type of carbon material derived from discarded face masks. The resulting hybrid material was used to modify a glassy carbon electrode, which was then used as the working electrode in the biosensor. The biosensor was designed to detect the presence of pazopanib by measuring the changes in current that occur when the drug binds to a complementary DNA strand that is immobilized on the electrode surface. The researchers found that the biosensor was highly sensitive to pazopanib, with a detection limit of 0.1 nM. This biosensor has potential applications in the field of cancer diagnosis and treatment, as it provides a simple and sensitive method for

Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral…

237

Fig. 7  Live/dead fluorescence images after spheroid treatment of 10 μg/mL of SnO2 and SASnO2 NPs treated with 72 h (Karthikeyan et al., 2023)

detecting pazopanib in biological samples. Additionally, the use of waste mask carbon in the synthesis of the hybrid material highlights the potential for sustainable and environmentally friendly approaches to material synthesis. In addition, this technology could potentially be adapted for use in COVID-19 diagnostics by modifying the biosensor to detect specific viral proteins or genetic material. However, further research and development would be necessary to apply this technology to COVID-19 detection.

COVID-19 Applications SnO2 is a material that has been studied for its potential applications in virus detection. SnO2 nanoparticles have been found to be effective in detecting viruses due to their unique surface properties, which can interact with the virus and change the electrical properties of the material. This change in electrical properties can be measured and used to detect the presence of the virus. Additionally, SnO2 nanoparticles can be functionalized with specific antibodies or proteins that can target and bind to specific viruses, making them a promising tool for virus detection and diagnosis. The recent research that proposed the novel method for detecting the spike protein of the SARS-CoV-2 virus using SnO2-xNx-based tpod nanostructures is an example of how SnO2 can be used in virus detection (Sharma et  al., 2023). The researchers functionalized the SnO2-xNx nanostructures with antibodies specific to

238

K. Chandrasekaran et al.

the SARS-CoV-2 spike protein. When the spike protein binds to the functionalized SnO2-xNx nanostructures, it causes a change in the electrical properties of the material, which can be detected using a simple electronic circuit. The researchers found that this method was highly sensitive and specific to the SARS-CoV-2 spike protein, detecting it at concentrations as low as 1 pg/mL. This method has potential applications in rapid and accurate diagnosis of COVID-19 infections. Rashed et al. discuss the development of a specialized water filtration membrane that utilizes carbon nanotubes and an antiviral metal oxide coating to capture the human coronavirus 229E (Rashed et al., 2023). The membrane is designed to be highly effective in removing viruses from water sources, making it a potentially valuable tool in the fight against waterborne illnesses. The metal oxide coating used in this study is made of SnO2, which has been shown to have strong antiviral properties. When applied to the carbon nanotube membrane, the SnO2 coating enhances its virus-capturing capabilities by effectively trapping and neutralizing the virus particles. Overall, this research demonstrates the potential of using advanced materials and coatings to create highly effective water filtration systems for virus removal. AbdelHamid et al. reported the development of a highly sensitive electrochemical sensor based on SnO2 for detecting chloroquine, a drug that has been used to treat COVID-19 (AbdelHamid et  al., 2023). The sensor was found to be highly accurate and sensitive, with a detection limit of 0.1  ng/mL.  In this study, the researchers used SnO2 nanoparticles to fabricate the electrochemical sensor, which was able to detect chloroquine by measuring the changes in electrical current as the drug bound to the sensor surface. This study demonstrates the potential of SnO2-­ based electrochemical sensors for detecting chloroquine (a COVID-19 drug) and other drugs, which could have important applications in health care and drug development.

Future Use The antibacterial, antimicrobial, and anticancer properties of SnO2 nanoparticles hold great potential for various applications in the biomedical industry. Here are some future uses of SnO2 NPs in this field: Antimicrobial Coatings: SnO2 NPs can be incorporated into coatings for medical devices, implants, and surfaces in healthcare settings. These coatings can help prevent the growth and colonization of bacteria, reducing the risk of infections associated with medical procedures and equipment. Wound Healing: SnO2 NPs can be utilized in wound dressings and topical formulations to prevent or treat bacterial infections in wounds. Their antimicrobial properties can help inhibit the growth of bacteria and promote the healing process. Drug Delivery Systems: SnO2 NPs can be functionalized or loaded with antimicrobial drugs to enhance their delivery and efficacy. These nanoparticles can serve

Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral…

239

as carriers for targeted drug delivery to specific sites of infection, enabling controlled and localized release of antimicrobial agents. Antibacterial Nanocomposites: SnO2 NPs can be incorporated into polymer nanocomposites for medical applications, such as surgical sutures, bone scaffolds, and tissue engineering. SnO2 NPs in these materials can impart antimicrobial properties, reducing the risk of infections and improving patient outcomes. Antimicrobial Nanoparticles in Combination Therapies: SnO2 NPs can be combined with other antimicrobial agents, such as antibiotics or antifungal drugs, to enhance their effectiveness against resistant bacterial strains or biofilms. The synergistic effects of these combined therapies can help overcome microbial resistance and improve treatment outcomes. Infection Control in Medical Environments: SnO2 NPs can be utilized in air filtration systems, surface coatings, and disinfectants to control the spread of infections in healthcare facilities. These nanoparticles can help inactivate or eliminate bacteria, viruses, and other pathogens, creating a safer environment for patients and healthcare workers. Targeted Drug Delivery: SnO2 NPs can be functionalized and utilized as drug carriers to deliver anticancer drugs specifically to tumor cells. The surface of SnO2 NPs can be modified to enhance their targeting ability, allowing for the selective delivery of therapeutic agents to cancer cells while minimizing damage to healthy cells. Photodynamic Therapy: SnO2 NPs possess excellent photocatalytic properties, making them ideal candidates for photodynamic therapy. By irradiating SnO2 NPs with the light of a specific wavelength, they can generate ROS that induce cytotoxic effects on cancer cells, leading to their destruction. This targeted therapy has the potential to minimize off-target effects and improve treatment outcomes. Combination Therapy: SnO2 NPs can be employed with other therapeutic modalities, such as chemotherapy or radiotherapy, to enhance their efficacy. The unique properties of SnO2 NPs, such as their ability to generate ROS and their high surface area for drug loading, make them suitable candidates for synergistic combination therapy approaches, resulting in improved cancer cell killing and reduced drug resistance.

Conclusion Industrially significant SnO2 nanoparticles have been shown to have a variety of medical applications, including their use as photocatalytic agents, antibacterial and antifungal agents, and anticancer agents. These nanoparticles possess several unique properties, such as high thermal stability, excellent electrical conductivity, strong oxidizing potential, chemical stability, corrosion resistance, low toxicity, and improved optical properties. The form and shape of SnO2 nanoparticles play a crucial role in determining their antimicrobial function, and modifications can be made

240

K. Chandrasekaran et al.

to develop nanoparticles with the desired medical application. SnO2 nanoparticles have potential medical applications, including virus detection and treatment. Recent research has shown their effectiveness in detecting viruses and enhancing water filtration systems for virus removal. SnO2-based electrochemical sensors have also been developed for detecting COVID-19 drugs and other drugs. However, further research is needed to understand the potential risks and develop safety guidelines fully. Overall, SnO2 nanoparticles hold promise as a valuable tool in the fight against COVID-19 and other viral infections. Acknowledgments Kokkarachedu Varaprasad received support from the Fondecyt Project 1211118, ANID, Chile.

References AbdelHamid, A., Elgamouz, A., Khanfer, M., & Kawde, A.-N. (2023). COVID-19 chloroquine drug detection using novel, highly sensitive SnO2-based electrochemical sensor. Arabian Journal of Chemistry, 16(5), 104674. https://doi.org/10.1016/j.arabjc.2023.104674 Ahmed, A. S., Azam, A., Muhamed Shafeeq, M., Chaman, M., & Tabassum, S. (2012). Temperature dependent structural and optical properties of tin oxide nanoparticles. Journal of Physics and Chemistry of Solids, 73(7), 943–947. https://doi.org/10.1016/j.jpcs.2012.02.030 Al-Hada, N., Kamari, H., Baqer, A., Shaari, A., & Saion, E. (2018). Thermal calcination-based production of SnO2 Nanopowder: An analysis of SnO2 nanoparticle characteristics and antibacterial activities. Nanomaterials, 8(4), 250. https://doi.org/10.3390/nano8040250 Bagheri-Mohagheghi, M.-M., Shahtahmasebi, N., Alinejad, M.  R., Youssefi, A., & Shokooh-­ Saremi, M. (2008). The effect of the post-annealing temperature on the nano-structure and energy band gap of SnO2 semiconducting oxide nano-particles synthesized by polymerizing– complexing sol–gel method. Physica B: Condensed Matter, 403(13–16), 2431–2437. https:// doi.org/10.1016/j.physb.2008.01.004 Bilge, S., Dogan Topal, B., Gokhan Caglayan, M., Altay Unal, M., Nazır, H., Bellur Atici, E., Sınağ, A., & Ozkan, S.  A. (2023). SnO2 nanoparticles/waste masks carbon hybrid materials for DNA biosensor application on voltammetric detection of anti-cancer drug pazopanib. Bioelectrochemistry, 150, 108329. https://doi.org/10.1016/j.bioelechem.2022.108329 Chávez-Calderón, A., Paraguay-Delgado, F., Orrantia-Borunda, E., & Luna-Velasco, A. (2016). Size effect of SnO2 nanoparticles on bacteria toxicity and their membrane damage. Chemosphere, 165, 33–40. https://doi.org/10.1016/j.chemosphere.2016.09.003 Chen, D., Huang, S., Huang, R., Zhang, Q., Le, T.  T., Cheng, E., Hu, Z., & Chen, Z. (2018). Highlights on advances in SnO2 quantum dots: Insights into synthesis strategies, modifications and applications. Materials Research Letters, 6(9), 462–488. https://doi.org/10.1080/2166383 1.2018.1482837 Das, S., & Jayaraman, V. (2014). SnO2: A comprehensive review on structures and gas sensors. Progress in Materials Science, 66, 112–255. https://doi.org/10.1016/j.pmatsci.2014.06.003 Dheyab, M. A., Aziz, A. A., Jameel, M. S., & Oladzadabbasabadi, N. (2022). Recent advances in synthesis, modification, and potential application of tin oxide nanoparticles. Surfaces and Interfaces, 28, 101677. https://doi.org/10.1016/j.surfin.2021.101677 Doyan, A., Susilawati, Muliyadi, L., Hakim, S., Munandar, H., & Taufik, M. (2021). The effect of dopant material to optical properties: Energy band gap Tin Oxide thin film. Journal of Physics: Conference Series, 1816(1), 012114. https://doi.org/10.1088/1742-­6596/1816/1/012114 Evstropiev, S. K., Karavaeva, A. V., Petrova, M. A., Nikonorov, N. V., Vasilyev, V. N., Lesnykh, L. L., & Dukelskii, K. V. (2019). Antibacterial effect of nanostructured ZnO-SnO2 ­coatings:

Exploring the Medical Applications of SnO2 Nanomaterials: Antimicrobial, Antiviral…

241

The role of microstructure. Materials Today Communications, 21, 100628. https://doi. org/10.1016/j.mtcomm.2019.100628 Fakhri, A., Behrouz, S., & Pourmand, M. (2015). Synthesis, photocatalytic and antimicrobial properties of SnO2, SnS2 and SnO2/SnS2 nanostructure. Journal of Photochemistry and Photobiology B: Biology, 149, 45–50. https://doi.org/10.1016/j.jphotobiol.2015.05.017 Gebreslassie, Y. T., & Gebretnsae, H. G. (2021). Green and cost-effective synthesis of tin oxide nanoparticles: A review on the synthesis methodologies, mechanism of formation, and their potential applications. Nanoscale Research Letters, 16(1), 97. https://doi.org/10.1186/ s11671-­021-­03555-­6 Goyal, V., Singh, A., Singh, J., Kaur, H., Kumar, S., & Rawat, M. (2022). Biogenically structural and morphological engineering of Trigonella foenum-graecum mediated SnO2 nanoparticles with enhanced photocatalytic and antimicrobial activities. Materials Chemistry and Physics, 282, 125946. https://doi.org/10.1016/J.MATCHEMPHYS.2022.125946 Gu, F., Wang, S. F., Lü, M. K., Qi, Y. X., Zhou, G. J., Xu, D., & Yuan, D. R. (2003). Luminescent properties of Mn2+−doped SnO2 nanoparticles. Inorganic Chemistry Communications, 6(7), 882–885. https://doi.org/10.1016/S1387-­7003(03)00135-­7 Haq, S., Shahzad, N., Shahzad, M. I., Elmnasri, K., Ali, M. B., Baazeem, A., Hedfi, A., & Ehsan, R. (2022). Investigations into the antifungal, photocatalytic, and physicochemical properties of Sol-Gel-Produced tin dioxide nanoparticles. Molecules, 27(19), 6750. https://doi.org/10.3390/ molecules27196750 Henry, J., Mohanraj, K., Sivakumar, G., & Umamaheswari, S. (2015). Electrochemical and fluorescence properties of SnO2 thin films and its antibacterial activity. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 143, 172–178. https://doi.org/10.1016/j. saa.2015.02.034 Huang, P.-H., Zhang, Z.-X., Hsu, C.-H., Wu, W.-Y., Ou, S.-L., Huang, C.-J., Wuu, D.-S., Lien, S.-Y., & Zhu, W.-Z. (2022). Deposition mechanism and characterization of plasma-enhanced atomic layer-deposited SnOx films at different substrate temperatures. Nanomaterials, 12(16), 2859. https://doi.org/10.3390/nano12162859 Karthikeyan, C., Varaprasad, K., Kim, S., Kumar Jangid, A., Lee, W., Syedahamed Haja Hameed, A., & Kim, K. (2023). Size-dependent cellular uptake of sodium alginate passivated tin dioxide nanoparticles in triple-negative breast cancer cells. Journal of Industrial and Engineering Chemistry, 123, 476–487. https://doi.org/10.1016/j.jiec.2023.04.001 Khan, S. A., Kanwal, S., Rizwan, K., & Shahid, S. (2018). Enhanced antimicrobial, antioxidant, in vivo antitumor and in vitro anticancer effects against breast cancer cell line by green synthesized un-doped SnO2 and Co-doped SnO2 nanoparticles from Clerodendrum inerme. Microbial Pathogenesis, 125, 366–384. https://doi.org/10.1016/J.MICPATH.2018.09.041 Meena Kumari, M., & Philip, D. (2015). Synthesis of biogenic SnO2 nanoparticles and evaluation of thermal, rheological, antibacterial and antioxidant activities. Powder Technology, 270, 312–319. https://doi.org/10.1016/j.powtec.2014.10.034 Mostafa, A. M., & Mwafy, E. A. (2020). Effect of dual-beam laser radiation for synthetic SnO2/Au nanoalloy for antibacterial activity. Journal of Molecular Structure, 1222, 128913. https://doi. org/10.1016/j.molstruc.2020.128913 Pinto, A. H., Nogueira, A. E., Dalmaschio, C. J., Frigini, I. N., de Almeida, J. C., Ferrer, M. M., Berengue, O. M., Gonçalves, R. A., & de Mendonça, V. R. (2022). Doped tin dioxide (d-SnO2) and its nanostructures: Review of the theoretical aspects, photocatalytic and biomedical applications. Solids, 3(2), 327–360. https://doi.org/10.3390/solids3020024 Rashed, A. O., Huynh, C., Merenda, A., Rodriguez-Andres, J., Kong, L., Kondo, T., Razal, J. M., & Dumée, L. F. (2023). Dry-spun carbon nanotube ultrafiltration membranes tailored by anti-viral metal oxide coatings for human coronavirus 229E capture in water. Journal of Environmental Chemical Engineering, 11(3), 110176. https://doi.org/10.1016/j.jece.2023.110176 Roopan, S.  M., Kumar, S.  H. S., Madhumitha, G., & Suthindhiran, K. (2015). Biogenic-­ production of SnO2 nanoparticles and its cytotoxic effect against hepatocellular carcinoma cell line (HepG2). Applied Biochemistry and Biotechnology, 175(3), 1567–1575. https://doi. org/10.1007/s12010-­014-­1381-­5

242

K. Chandrasekaran et al.

Sathishkumar, M., & Geethalakshmi, S. (2020). Enhanced photocatalytic and antibacterial activity of Cu:SnO2 nanoparticles synthesized by microwave assisted method. Materials Today: Proceedings, 20, 54–63. https://doi.org/10.1016/j.matpr.2019.08.246 Shahid, S., Zaman, S., Qamar, M. A., Shahid, S., Khan, S. A., Zaman, S., & Sarwar, M. N. (2017). Synthesis characterization, optical and antibacterial studies of Co-Doped SnO2 nanoparticles synthesis characterization, optical and antibacterial studies OF Co-doped SnO2 nanoparticles. Digest Journal of Nanomaterials and Biostructures, 12(4), 1127–1135. https://www.researchgate.net/publication/321367365 Sharma, A., Ahmed, A., Singh, A., Oruganti, S.  K., Khosla, A., & Arya, S. (2021). Review— Recent advances in tin oxide nanomaterials as electrochemical/Chemiresistive sensors. Journal of the Electrochemical Society, 168(2), 027505. https://doi.org/10.1149/1945-­7111/ABDEE8 Sharma, N., Chi, C.-H., Dabur, D., Tsai, A.  C.-C., & Wu, H.-F. (2023). SnO2-xNx based tpod nanostructure for SARS-CoV2 spike protein detection. Environmental Research, 234, 116505. https://doi.org/10.1016/j.envres.2023.116505 Varaprasad, K., Karthikeyan, C., KanikiReddy, V., Núñez, D., Sadiku, E. R., & Briones, R. (2020). Antibiotic nanomaterials. In Antibiotic materials in healthcare (pp. 1–10). Elsevier. https://doi. org/10.1016/B978-­0-­12-­820054-­4.00001-­X Varaprasad, K., Karthikeyan, C., Yallapu, M.  M., & Sadiku, R. (2022). The significance of biomacromolecule alginate for the 3D printing of hydrogels for biomedical applications. International Journal of Biological Macromolecules, 212, 561–578. https://doi.org/10.1016/j. ijbiomac.2022.05.157 Vidhu, V. K., & Philip, D. (2015). Biogenic synthesis of SnO2 nanoparticles: Evaluation of antibacterial and antioxidant activities. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 134, 372–379. https://doi.org/10.1016/j.saa.2014.06.131 Vijayalakshmi, R. V., Kuppan, R., & Kumar, P. P. (2020). Investigation on the impact of different stabilizing agents on structural, optical properties of Ag@SnO2 core  – Shell nanoparticles and its biological applications. Journal of Molecular Liquids, 307, 112951. https://doi. org/10.1016/j.molliq.2020.112951 Xiong, L., Guo, Y., Wen, J., Liu, H., Yang, G., Qin, P., & Fang, G. (2018). Review on the application of SnO2 in perovskite solar cells. Advanced Functional Materials, 28(35), 1802757. https://doi.org/10.1002/ADFM.201802757 Yan, L. Z., Fahmi Hawari, H., & Djaswadi, G. W. (2019). Highly sensitive SnO2-reduced graphene oxide hybrid composites for room temperature acetone sensor. In Proceedings – 2019 IEEE 15th international colloquium on signal processing and its applications, CSPA (pp. 71–74). https://doi.org/10.1109/CSPA.2019.8695987 Zhang, Y. (2018). Cell toxicity mechanism and biomarker. Clinical and Translational Medicine, 7(1), 1–6. https://doi.org/10.1186/S40169-­018-­0212-­7 Zhao, Q., Ma, L., Zhang, Q., Wang, C., & Xu, X. (2015). SnO2-based nanomaterials: Synthesis and application in lithium-ion batteries and Supercapacitors. Journal of Nanomaterials, 2015, 1. https://doi.org/10.1155/2015/850147 Zuorro, A., Dominguez, J. R., García Rodríguez, J., Peres, J. A., Frontistis, Z., Luisa Alves do Nascimento, J., Chantelle, L., Maria Garcia dos Santos, I., Luiz Menezes de Oliveira, A., & Cristina Ferreira Alves, M. (2022). The influence of synthesis methods and experimental conditions on the photocatalytic properties of SnO2: A review. Catalysts, 12(4), 428. https://doi. org/10.3390/CATAL12040428

NiO Nanoparticles for Advanced Clinical Applications Adil M. Allahverdiyev, Buşra Akgül, Jahid Alakbarli, Sedanur Keleş, Malahat Baghırova, and Emrah Ş. Abamor

Overview Properties of Nanoparticles Nanoparticles (NPs) are small particles ranging in size from 1 to 100 nanometers (nm). The decrease in NP size results in a change of properties such as quantum size effect, high surface area, and low sintering temperature. NPs separate from their bulk counterparts in a variety of physical and chemical properties resulting from their small size. These unique properties have led to the development of a wide range of applications in fields such as electronics, biomedicine, and energy storage (Khan et al., 2019; Murthy, 2007). One of the most important advantages of NPs is their high surface-to-volume ratio, which increases their reactivity and catalytic activity. The physical and chemical properties of NPs depend on their size and shape. The color or optical properties of NPs largely depend on the size of the particle. The melting point and phase transition temperature of NPs are low, and the band gap increases as the size of NPs A. M. Allahverdiyev (*) · M. Baghırova The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan B. Akgül · E. Ş. Abamor Department of Bioengineering, Yıldız Technical University, Istanbul, Turkey J. Alakbarli The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan Department of Bioengineering, Yıldız Technical University, Istanbul, Turkey S. Keleş Department of Metallurgical and Materials Engineering, Karadeniz Technical University, Trabzon, Turkey © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_11

243

244

A. M. Allahverdiyev et al.

decreases. In addition, the small sizes of NPs allow them to cross biological barriers such as cell membranes, making them highly effective in drug delivery and medical imaging applications. Furthermore, their optical and electronic properties make them useful in electronics and energy storage applications (Alkilany & Murphy, 2010; Khan et al., 2019; Pan et al., 2012). Despite their potential benefits, NPs can also pose potential risks to human health and the environment. For example, their small size may facilitate their entry into the human body through inhalation or ingestion, where they may interact with biological systems in ways that are not yet fully understood (Auffan et al., 2009). NPs can be synthesized from a variety of materials, including metals, metal oxides, polymers, and carbon-based materials, using various methods such as chemical synthesis, physical deposition, and biological methods. The choice of synthesis method and material significantly affects the properties of the resulting NPs (Khan et al., 2019; Pan et al., 2012). Top-down and bottom-up synthesis protocols have been adopted for nanoparticle synthesis methods. Nanoparticle production using plasma systems has also attracted great interest in recent years (Huang et al., 2015; Nguyen et al., 2020; Thanh et al., 2014). In addition, with the recent development of nanotechnology, the green synthesis method has been used in nanoparticle production. In this method, NPs are synthesized using various biological systems including yeast, actinomycetes, plant extracts, fungi, algae, and bacteria (Salem, 2023). The green synthesis mechanism of metal and metal oxide NPs takes place in three stages: activation stage, growth stage, and termination stage. In the activation stage, metal ions are reduced, and the reduced metal atoms undergo nucleation. In the growth phase, small adjacent NPs self-assemble to form larger sized nanoparticles. In this process, called Ostwald ripening, the thermodynamic stability of the NPs increases. In the finalization stage, the NPs take their final shape. To produce metal oxide, the final product is air-dried or air-calcined (Makarov et  al., 2014; Nguyen et al., 2020).

Nickel Oxide Nanoparticles Nickel oxide NPs (NiO NPs) are a new product with many properties, such as high level of surface energy, high magnetism, low melting point, high surface area, high reactivity, operational simplicity, biocompatibility, bacterial resistance, and anti-­ inflammatory activities. NiO NPs can be widely used in modern industries such as catalysts, sensors, heat exchangers, laser etching, and electronic applications. Their use in widespread applications in humans and the environment raises concerns associated with their toxicity. NiO NPs are also used in numerous biomedicine fields, including cell isolation, drug delivery, imaging, biosensors, and more (Ahghari et al., 2020; Imran Din & Rani, 2016; Jaji et al., 2020; Legmairi et al., 2023). Chemical vapor deposition (CVD), sol-gel, gas evaporation, microemulsion deposition, anodic arc plasma technique, polymer-matrix assisted synthesis, and

NiO Nanoparticles for Advanced Clinical Applications

245

green synthesis methods are used for the production of NiO NPs. In addition, NiO NPs can be chemically reacted in anhydrous and aqueous media and can be produced by sonication, radiolytic, and freeze/dry methods (Ba-Abbad et  al., 2015; Bora et al., 2017; Idris et al., 2021; Jafari et al., 2019; Kalita & Saikia, 2021; Wang et al., 2002). Green synthesis is the biosynthesis of nanomaterials from various biological wastes such as plant materials, microorganisms, and agricultural residues. The green synthesis method has the advantages of environmental friendliness, low cost, and simple process. Therefore, in the production of NiO-based nanometals, green synthesis is considered a faster and cheaper synthesis method (Gebretinsae et al., 2021; Mohammadi et al., 2018; Zhang et al., 2021). In recent years, studies on the production of NiO NPs by green synthesis have increased. NPs produced by green synthesis have different sizes and morphologies. Organic functional groups in plants play an active role as reducing, protective, and stabilizing agents in the production of nanoparticles. Nanomaterials prepared by this method have high polydispersity, well-defined dimensions, and thermodynamic stability. Green synthesis methods using plant exudates (leaf, fruit, flower, stem, and roots) are thought to be more suitable for the synthesis of nanomaterials (Fig. 1). Recent studies have successfully established the use of innovative NiO NPs for applications including cancer treatment, antibacterial activity, drug transport, antioxidant activity, catalysis, and the removal of hazardous chemicals from wastewater (Barabadi et al., 2017; Martín-­ Camacho et al., 2022; Nath et al., 2016; Ullah et al., 2020). In the synthesis of NiO nanoparticles, plants such as fresh tea leaf extract, Solanum torvum unripe fruit, Coriandrum sativum, Rheum turkestanicum, Eichhornia crassipes, and Opuntia ficus indica are used (Kalita & Saikia, 2021; Renuka et al., 2021; Saheb et al., 2019; Sarkar et al., 2020; Zhang et al., 2021). Fig. 1  Schematic diagram of green synthesized metal oxide NPs using plant exudates

246

A. M. Allahverdiyev et al.

Advantages and Disadvantages Advantages High surface area: The high surface area increases the catalytic activity of the material, especially in chemical reactions, as the interaction area increases. In particular, it improves the electrical, optical, and mechanical properties of NiO NPs (Ahmed et al., 2019; Sahoo et al., 2023). Thermal stability: Thanks to thermal stability, no change is observed in the structure of materials under temperature change. Thanks to their thermal stability, NiO NPs provide the advantages of long life, durability, and use in high-temperature applications (Ghosal et al., 2019; Mala et al., 2022). Cost-effective synthesis: The ability to synthesize NiO NPs with high efficiency at low costs increases their use in various fields. Especially, sol-gel, green synthesis, and hydrothermal synthesis are the preferred methods to produce NiO at low cost (Dadkhah & Tulliani, 2022; Dehno Khalaji et al., 2018). Antimicrobial effect: NiO NPs show antimicrobial properties against a wide range of microorganisms, including bacteria, fungi, and viruses. They show antimicrobial activity through various mechanisms, such as their ability to interfere with intracellular metabolism, their ability to produce reactive oxygen species (ROS) that can cause oxidative damage in cells, leading to cell death, and DNA damage (Narender et al., 2022; Sana et al., 2021). Disadvantage Toxicity: The damage mechanisms caused by NiO NPs in cells cause toxicity. Therefore, inhalation, dermal, or oral ingestion of NiO NPs may pose a threat to health (Lingaraju et al., 2020; Shwetha et al., 2021). For this reason, in addition to its advantages, its use in biomedical applications, especially due to the toxic effect it exhibits, causes some concerns.

Toxicity Effect (a Mechanism) on Living Cells Toxicity is the potential of a substance to cause disruption of the body’s chemical and biological functions. This property can damage individual organs, tissues, cells, or the whole body. Cytotoxicity tests are used to detect cell viability after cytotoxicity, which is determined by the accuracy of the data and the cost, speed, and complexity of the required equipment. Many methods have been developed to evaluate the viability of cells after cytotoxicity, with each method having its advantages and disadvantages (Allahverdiyev, 2018; Erman Salih Istifli. & Hasan Basri Ila., 2019; Stoddart, 2011). Toxicologists are investigating the toxicological effects of exposure to NPs due to their larger surface area-to-volume ratio, small size, and ability to absorb toxic metals. The most important factors affecting the toxicity of materials are particle size and morphology. Toxicity studies in animal models and in cell cultures have

NiO Nanoparticles for Advanced Clinical Applications

247

shown that the toxic effect of NPs is greater than the toxic effect of large particles (Peng et al., 2011; Veranth et al., 2007). Nanotechnology has led to the development of NPs that can interact with the biological environment. Metal oxide and metal NPs can be hazardous to humans due to their catalytic activity and decomposition, which can increase the ion concentration and interfere with cell metabolism. In order to comprehend the health effects of these NPs, it is essential to conduct a study of their chemical composition and physical characteristics for the assessment of potential risks. The dose–effect relationships of these NPs are contingent upon their interaction with biological substances, including proteins, cell membranes, and cell receptors present in biological fluids. Metal oxide NPs exhibit numerous advantageous characteristics, including high efficiency, facile synthesis, modifiability, and catalytic activity, owing to their porous structure, which imparts exceptional thermal and chemical stability, as well as a substantial surface area. Metal oxide NPs exhibit promising potential in the realm of disease treatment and pathogen control. Cell proliferation, migration, signaling, and wound healing are the significant biological roles played by ROS. The reactive species generated by metal oxide NPs not only induce an inflammatory response but also have the potential to induce oxidative stress beyond a certain threshold, leading to the eventual apoptosis of healthy cells. Long-term inhalation of nickel oxide nanoparticles, one of the metal oxide NPs, can lead to the development of lung cancer and tissue inflammation (Drummer et  al., 2021; Llop et  al., 2014; Lu et al., 2015; Nikolova & Chavali, 2020; Soltys et al., 2021; Ullah et al., 2020). The toxic effect of NPs on cells has led to their use in cancer treatment. Because of this, most of the studies in the literature examining the toxicity effects of NiO NPs have been carried out using cancer cells. In a study, Shwetha et al. examined the cytotoxic properties of synthesized NiO NPs on human lung cancer cells (Shwetha et al., 2021). The cytotoxicity assay was conducted on NiO NPs synthesized through biosynthesis. The assay was performed on the A549 human lung cancer cell line using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay. The evaluation of the cytotoxicity of NiO NPs against A549 cell line was conducted by analyzing the cellular reduction of MTT during in vitro experiments. Following exposure to various concentrations, the efficiency of A549 cells exhibited a decline, resulting in a reduction in the formation of cancer cells. Lingaraju et al. synthesized NiO NPs using aqueous leaf extract of the medicinal plant Euphorbia heterophylla (Lingaraju et al., 2020). The biosynthesized NiO NPs were investigated for their cytotoxicity against human lung cancer (A549) and human hepatocarcinoma (HepG2) cell lines. The cytotoxicity of different concentrations of NiO NPs against human cancer cell lines was evaluated using MTT assay. Results showed the decrease of cell viability with increasing the concentration of NiO NPs, ultimately leading to apoptosis. Sabouri et al. developed a novel synthesis method for the preparation of NiO NPs using a plant extract derived from okra and nickel nitrate hexahydrate (Sabouri et  al., 2019). The cellular cytotoxicity investigations of the NiO NPs have been conducted on various tumor cells using the MTT assay. The findings from the

248

A. M. Allahverdiyev et al.

cytotoxicity analysis indicate a significant decrease in cell viability percentage. The observed effects were found to exhibit toxicity at elevated concentrations, while displaying minimal impact at lower concentrations. In a separate investigation carried out by Sabouri et al., the utilization of nickel nitrate hexahydrate as the nickel precursor and fresh egg white (EW) as the stabilizing agent was employed for the synthesis of NiO NPs (Sabouri et  al., 2020). The MTT assay was employed to examine the impact of the synthesized NiO NPs on the metabolic activity of U87MG cells, thereby evaluating their cytotoxicity. The findings of the research studies revealed that the presence of NiO NPs had detrimental impacts on the proliferation of U87MG cells. Furthermore, the concentration of NiO NPs necessary to impede 50% of cell growth (IC50) within a 48-hour timeframe was approximately 15.62 g/ mL. The results of this study indicate that NiO NPs may serve as a viable substitute for conventional cancer therapies. Abudayyak et al. investigated the effect of NiO NPs on human intestinal epithelial cells (Abudayyak et al., 2020). The evaluation of the toxicity of NiO NPs was conducted by employing the Caco-2 human intestine cell line, which is extensively differentiated human cell line. The cytotoxicity of NiO NPs was assessed through the utilization of MTT and neutral red uptake (NRU) assays. The cytotoxicity evaluation yielded findings indicating a correlation between concentration levels and a reduction in cell viability. The study findings indicate that exposure to NiO NPs resulted in the occurrence of DNA damage. Hence, it is recommended that additional investigations be undertaken to elucidate the toxicological properties of NiO NPs and to provide a comprehensive understanding of the mechanisms underlying apoptosis and DNA damage. Siddiqui and coworkers examined the potential toxicity, oxidative stress, and apoptosis-inducing effects of NiO NPs on human airway epithelial (HEp-2) and human breast cancer (MCF-7) cells (Siddiqui et al., 2012). The examination of curcumin’s potential to mitigate these effects was conducted. The cells were subjected to a concentration of 25 g/mL of NiO NPs for a duration of 24 h, with the option of being exposed to curcumin at a concentration range of 15–25 M. The findings of the study demonstrated that the concurrent exposure to curcumin effectively mitigated the adverse impact on cell viability caused by NiO NPs. Additionally, it was demonstrated that the compound exhibited a reduction in the cytotoxic effects caused by NiO NPs in both HEp-2 and MCF-7 cell lines. This study posits that curcumin exhibits potential as a preventive agent against the toxicity induced by NiO NPs. The synthesis of NiO NPs was conducted by Haritha et al. using Averrhoa bilimbi as the precursor (Haritha et al., 2022). An MTT assay was conducted to assess the cytotoxicity of biosynthesized NiO NPs against HCT116 cancer cells and L929 fibroblast cells. The cytotoxic effects of NiO NPs on breast cancer cells and human colorectal cancer cells have been investigated in previous studies. The toxicity of the material is significantly influenced by factors such as the size, shape, and surface-­to-volume ratio of the produced nanoparticles. The results of this study demonstrated that the NPs generated exhibited a lower level of cytotoxicity toward normal cells in comparison with breast cancer cells.

NiO Nanoparticles for Advanced Clinical Applications

249

Antiviral (COVID-19) and Antimicrobial Characteristics Antibacterial Characteristics of NiO Nanoparticles Many studies have discovered that NiO NPs exhibit antibacterial action; however, the mechanisms by which microorganisms are affected are still unclear. Many experts, however, believe in three key mechanisms: the creation of ROS in cells, which causes tremendous damage to bacteria, the release of ions, and the adsorption of NPs on the cellular membranes (Narender et al., 2022). The antibacterial action mechanism of NiO NPs is illustrated in Fig. 2. In research done by Thirbika et al., the antibacterial activity of produced NiO NPs was investigated using the well-­ diffusion technique against two gram-positive bacteria, Streptococcus pneumoniae (S. pneumoniae) and Staphylococcus aureus (S. aureus) (Thirbika et al., 2022). The results revealed that NiO NPs have outstanding antibacterial capabilities, which might be attributed to their capacity to impede cell wall synthesis, depolarize the cellular membrane, and damage nucleic acid and protein synthesis. Gram-positive bacteria are more vulnerable to harm due to their multilayered peptidoglycan structure, and the NiO NPs may have done damage to their cellular membrane. Overall, the antibacterial activity of the biosynthesized NiO NPs against the investigated bacterial strains was encouraging. In another study by Shanan and Shanshool, NiO NPs are synthesized using plant extracts from Matricaria chamomilla L., Camellia sinensis, Punica granatum L. peel., and Artemisia herba-alba Asso (Shanan &

Fig. 2  Schematic representation of antibacterial action mechanism of NiO NPs

250

A. M. Allahverdiyev et al.

Shanshool, 2023). They also looked at the antibacterial properties of these NPs. It was revealed how plant extracts facilitated the production of NiO NPs. X-ray diffraction, energy-dispersive X-ray analysis, scanning electron microscopy, UV-visible spectrophotometry, Fourier transform infrared spectroscopy, and Zeta potential analysis were used to characterize the produced green NiO NPs. The NiO NPs demonstrated strong antibacterial action against both gram-positive and gram-­ negative bacteria and fungi. In a study done by Nazaripour et al., Rosemary extract was used to synthesize ferromagnetic NiO NPs at pH 8.3 (Nazaripour et al., 2022). The NiO NPs exhibited a spherical shape and a homogenous size distribution. The minimum inhibitory concentration (MIC) of NPs against Streptococcus mutans (S. mutans), a bacteria implicated in tooth-rotting, was determined. S. mutans causes dental enamel degradation by fermenting sugar and producing lactic acid. The MIC of the NPs was determined to be ≥500  μg/mL.  Because of their antioxidant characteristics, plant phenols in Rosemary extract improved the bacteriostatic activities of NiO NPs. According to the findings, nickel composite alloys containing NiO NPs might be utilized to make dental amalgam. The antimicrobial property of NiO NPs was linked to the synergistic action of Rosemary extract and the NP characteristics. The study emphasizes the prospects of biogenic NiO NPs for dental uses. Another study done by Gupta et al. focused on the antibacterial properties of NiO NPs compared to bulk NiO and standard antibiotics (Gupta et al., 2020). NiO NPs were synthesized and characterized, and their antibacterial activity against S. aureus and E. coli at different doses was tested. The results revealed that NiO NPs were more effective against S. aureus than E. coli at the same dose. At all doses examined, NiO NPs outperformed bulk NiO in antibacterial activity. At low quantities, the conventional antibiotics tetracycline and gentamicin had little impact. The physical and chemical characteristics of NPs were strongly altered by their size, shape, and concentration, impacting bacterial growth and sustainability. NiO NPs having a spherical form and an average size of 40–55 nm displayed promising antibacterial activity. The antibacterial effect of the NPs was linked to a variety of factors, such as oxidative stress, cellular membrane lysis, enzyme inhibition, and proteolysis. The positively charged exterior of NiO NPs interacted with the negatively charged surface of the cell membrane, resulting in cellular inactivation, penetration, and the formation of ROS. The reduced size of NiO NPs increased their dispersibility, passage into the intracellular matrix, and interaction with intracellular activities. The NPs broke the cell membrane, causing damage to cell components and further penetrating the cell, culminating in organelle leakage. These combined processes improved the antibacterial activity of the NPs. Metal oxide NPs, such as NiO, were thought to be reasonable alternatives to antibiotics that did not cause bacterial resistance. The study found that NiO NPs have significant antibacterial activities and indicated that they may be used in the biomedical sector and other fields to treat microbial infections and diminish antibiotic resistance. Metal and metal oxide NPs have been studied for their scolicidal action against microorganisms associated with hydatid cysts. Various NPs have been studied, including silver (Ag), copper (Cu), zinc oxide (ZnO), and NiO.  These NPs have

NiO Nanoparticles for Advanced Clinical Applications

251

antibacterial capabilities and have been studied for their ability to disinfect and eliminate microorganisms. The study done by Shnawa et al. focused on the antiparasitic effect of NiO NPs synthesized using the leaf extract of Ziziphus spina-christi L. NiO NPs were found to have scolicidal efficacy against Echinococcus granulosus protoscoleces, highlighting their potential for treating hydatid cyst illness (Shnawa et al., 2022). Electrostatic interactions, oxidative stress creation, membrane damage, oxidative stress, and DNA degradation were identified as the mechanisms of action. NiO NPs caused bacterial mortality by producing ROS such as hydrogen peroxide. The positive charge of the surface of NiO NPs attracted the negatively charged cell wall of bacteria, causing membrane rupture and cytoplasmic damage. The increased surface area and NP size boosted the antibacterial activity even further. Previous research has also shown that NiO NPs had significant antibacterial action against gram-positive and gram-negative bacteria (Angel Ezhilarasi et  al., 2018; Prabhu et al., 2022; Uddin et al., 2021; Vijaya Kumar et al., 2019). Nickel ions generated by NiO NPs pierced the cell wall of bacteria, causing DNA, protein, and mitochondrial damage, ultimately resulting in cell death. The size of the NPs was discovered to affect their antibacterial action, with smaller NPs being more effective. Furthermore, electrostatic forces, the production of Ni2+, and the emission of ROS were identified as probable processes underlying the bactericidal effect of NiO NPs. Habtemariam et al. synthesized NiO NPs using a low-cost and environmentally friendly approach that used Rhamnus prinoides leaf extract as a reducing and stabilizing agent (Habtemariam & Bekele, 2022). The NPs produced have a face-­centered cubic shape. The antimicrobial effect of the produced NiO NPs was tested against gram-positive and gram-negative bacteria. Escherichia coli (E. coli) and Salmonella typhimurium were effectively inhibited by the growth suppression of NPs. The activity index, determined based on the inhibition diameter, demonstrated that the produced NiO NPs inhibited gram-negative bacterial growth. Ali et al. focused on the green synthesis of Ni and NiO NPs using Lactuca serriola seed extract in another research (Ali et al., 2022). The antibacterial activity of Ni/NiO NPs against pathogenic bacteria, such as S. aureus, Staphylococcus epidermidis (S. epidermidis), Pseudomonas aeruginosa (P. aeruginosa), and E. coli, was investigated. The antibacterial action of NPs was seen at low dosages, and nearly complete suppression of bacterial growth was obtained at higher optimum concentrations. Alteration to the cell membrane, interruption of food intake, and ionization processes were all implicated in the antibacterial action mechanism. ROS such as hydroxyl radicals, superoxide radicals, singlet oxygen, and hydrogen peroxide were produced by the NPs, causing damage to cell membranes, mRNA, DNA, ribosomes, peptidoglycan, and proteins. Bacteriostatic activity was seen at low doses and bactericidal activity at higher values. Furthermore, the NPs displayed outstanding photocatalytic activity and degradability, making them appropriate for environmental remediation applications. Haritha et al. synthesized NiO NPs by reducing and capping them with Averrhoa bilimbi fruit extract (Haritha et al., 2022). The NPs were found to have significant antibacterial action against E. coli and S. aureus, with a greater zone of inhibition

252

A. M. Allahverdiyev et al.

detected at a dosage of 150 μg/mL. Antibacterial activity was stronger against gram-­ negative bacteria. Particle size, precursor concentration, solution pH, and surface flaws of the produced NPs may all contribute to the antibacterial action. The ROS produced by NPs interacted with multiple biological components, causing cell death. In comparison with prior publications, the produced NiO NPs displayed stronger antibacterial activity. This study demonstrates the antibacterial properties of NiO NPs and recommends applications in medical and industrial environments. A study done by Rajith Kumar et al. investigated the antibacterial action mechanism of NiO NPs that were synthesized using the leaves extract of Calotropis gigantea through a solution combustion method (Rajith Kumar et al., 2020). The NiO NPs demonstrated improved photodegradation of methylene blue dye and antibacterial action against S. aureus and E. coli. The antibacterial effect of NiO NPs was linked to the Fenton process, which produces ROS. ROS chemicals such as hydroxyl radicals, superoxide radicals, singlet oxygen, and alpha-oxygen harmed lipids, DNA, and proteins, causing bacterial eradication. The zone of inhibition experiment revealed that the NiO NPs inhibited both bacterial strains significantly more than the usual antibiotic, ciprofloxacin. In research by Rehman et al., NiO NPs were synthesized using Bergenia ciliate leaf extract as a reducing and capping agent (Rehman et al., 2021). The antibacterial activity of NiO NPs was examined against E. coli and S. aureus, with more activity seen against gram-negative than gram-positive bacteria. The antibacterial effectiveness of NiO NPs improved with increasing concentration. The greater inhibitory zone reported for gram-negative bacteria might be related to changes in cell wall content and surface charges. NiO NPs were able to permeate the bacterial cell, disrupting cytoplasmic function and inhibiting the respiration process. The release of free Ni2+ from the NPs was hypothesized to assist the antibacterial action. Overall, the work emphasizes the environmentally friendly production of NiO NPs using plant extract and their prospective uses in wastewater purification, bacterial growth suppression, and free radical scavenging. The multifunctional qualities of NiO NPs make them excellent candidates for a variety of potential uses.

Antiviral Characteristics of NiO Nanoparticles Nanomaterials have high potential to be used as antimicrobial and antiviral due to their large surface area, functional ability, and good physical and biological properties. When the antiviral properties of NiO NPs, which are nanostructured and oxidized metallic materials, are examined, it has been observed that they are generally used in the control of plant viruses. In the literature, there are studies in which NiO nanostructures are not directly but indirectly interacted with COVID-19. The antiviral activity of NiO nanostructures directly on SARS-CoV-2 has not been examined. Since the bio-persistence of NiO NPs in the lung is higher than other NPs, they can cause chronic inflammation

NiO Nanoparticles for Advanced Clinical Applications

253

for 1 to 3 months. They can also remain in the lungs for up to 6 months (Chang et al., 2018; Oyabu et al., 2017). In previous studies, it has been reported that their persistence in the lung causes acute neutrophilic inflammation through the activation of NLRP3 inflammasomes and ROS production (Cao et al., 2016; Cho et al., 2012). Probably for these reasons, NiO NPs have not been included in SARS-­ CoV-­2-related research targeting the lung. It is known that the production and use of surgical masks increased during the COVID-19 pandemic to reduce the risk of transmission (Lee et  al., 2021). Accordingly, the idea of recycling used masks was considered important by some scientists. Li et  al. suggested that an environmentally friendly and cost-effective way of recycling waste masks was necessary (Li et al., 2022). In their study, they transformed waste masks into carbon–nickel composite nanowires. It was found that the nanowires they obtained have high conductivity, small pore size, and large surface area and can also be used as a high-performance lithium battery anode.

Recent Studies on Antimicrobial and Antiviral Applications The current interest in developing new antimicrobial agents is due to increasing bacterial resistance and emerging pathogens, but many problems remain unresolved for most existing treatments (Suresh et  al., 2016). Researchers have reported the antimicrobial activity of metal oxide nanoparticles, but the mechanism by which they kill microorganisms is unclear. Three main mechanisms are ROS formation, ions release, and adsorption of NPs on the cell membrane (Narender et al., 2022). Metal oxide NPs can be used as antimicrobial agents due to their low toxicity and heat resistance, as well as their activity on resistant strains of microbial pathogens. NiO NPs have the highest antimicrobial activities due to their high toxicity to cells and small size. Moreover, the existence of extracellular Ni2+ has the capacity to disrupt intracellular Ca2+ metabolism and induce cellular harm. The bactericidal efficacy of these NPs is contingent upon their dimensions, stability, and concentration when introduced into the growth medium (Khashan et al., 2017). NiO NPs have promising traits such as biocompatibility, thermal and chemical stability, and optical characteristics, and have also improved their bactericidal effects (Zarenezhad et al., 2022). NiO NPs have potential for various antibacterial applications due to their antibacterial properties, which are outlined in recent articles. Mirza et  al. reported a biomediated ecofriendly method for the synthesis of nickel oxide NPs using plant extracts (Mirza et  al., 2021). This study aimed to investigate the antibacterial activity of nanomaterials and plant extracts against both gram-positive and gram-negative pathogenic bacteria. The agar well-diffusion method was employed to investigate the antibacterial activity against both gram-­ positive and gram-negative bacterial strains. According to the bioassay results, both NiO NPs and NiO NPs C-points were found to be potent against all bacterial strains. As a result, it was suggested that this method is a sustainable and economical approach for the synthesis of metal oxide nanoparticles.

254

A. M. Allahverdiyev et al.

According to Nikolova and Chavali, it was observed that NiO NPs exhibited both bactericidal and bacteriostatic effects, with the specific outcome being dependent on the bacterial species and concentration (Nikolova & Chavali, 2020). The antibacterial efficacy of the NiO nanocomposite prepared at a concentration of 100 g/mL was observed to be marginally less potent against gram-negative strains (E. coli and Vibrio cholerae) compared to the standard antibiotic, streptomycin. Following the process of surface functionalization, the bactericidal activity against S. aureus and P. aeruginosa, as well as the antifungal activity of 5-amino-2-­mercaptobenzimidazole NiO NPs, exhibited an enhancement when compared to the non-functionalized NiO NPs. The observed discrepancy was elucidated by the improved dispersibility of the modified nanoparticles, as described by the authors. The interaction between NiO NPs and sulfur and phosphorus components of bacterial DNA, as well as other functional groups found in proteins, has been demonstrated. This interaction has been observed to result in protein leakage and subsequent bacterial mortality. The bactericidal activity of green synthesized NiO NPs, which were subjected to annealing at various temperatures, was observed to be moderate against suspensions of microbial pathogens, namely, S. aureus and E. coli. The growth of both strains was not completely inhibited by the NiO NPs. In a study by Helan et al., NiO NPs were synthesized using neem leaves and were tested against S. aureus and E. coli (Helan et al., 2016). NiO NPs were found to penetrate the cell wall of the strains and alter the cellular membrane and inner cellular components, leading to cell death. Additionally, the applicational bacterial analysis of NiO confirmed that the synthesized nanoparticle consists of nanoholes with various pore sizes, which lead to heat treatment by precursor. These findings suggest that NiO NPs can be used to suppress microbial pathogens such as S. aureus and E. coli. Kannan et  al. synthesized NiO NPs using Limonia acidissima Christm (citrus fruit juice) as fuel by a microwave-assisted method (Kannan et al., 2020). The NPs were subjected to analysis in order to investigate their morphological, structural, and optical characteristics. Additionally, their efficacy as antibacterial agents was evaluated against various bacterial strains, including S. aureus, P. aeruginosa, E. coli, and Klebsiella pneumonia (K. pneumonia). In this investigation, the nanoparticle concentration was manipulated within the range of 50 to 100 g/mL, resulting in significant antibacterial efficacy against the targeted pathogens. The antibacterial activity of NiO NPs is observed to be notably higher against E. coli, while demonstrating moderate activity against S. aureus. The NiO NPs that were prepared exhibited the release of Ni2+ on their surface, which subsequently interacted with the membranes of microbial cells. This interaction resulted in the bactericidal effect, which can be attributed to the transmission of nutrients facilitated by the proteins formed during this process. Another study examining the antibacterial properties of NiO NPs produced by biosynthesis was conducted by Likasari et al. (2021). This study investigated the antibacterial efficacy of NiO NPs that were synthesized using an extract derived from the leaves of Tagetes erecta L. The antibacterial potential of these NPs was evaluated against four bacterial strains, namely, K. pneumoniae, E. coli, S. aureus, and Streptococcus pyogenes. The inhibitory efficacy of NiO NPs was found to be

NiO Nanoparticles for Advanced Clinical Applications

255

more potent compared to ampicillin, which was used as the positive control antibiotic. The observed increase in the inhibition zone with an extended incubation time suggests that the NPs possess bactericidal properties, as they not only inhibit the growth of bacteria but also induce bacterial cell death. The physicochemical characteristics, chemical properties, and biological properties of the synthesized NiO NPs demonstrate the significant potential of these green synthesized NiO NPs for future environmental applications. Khodair et  al. prepared an environmentally friendly NiO NPs by combining nickel nitrate salt with orange leaf extract (Khodair et al., 2022). The antimicrobial efficacy of the synthesized NiO NPs was assessed through the utilization of the agar diffusion method against E. coli and S. aureus. The NiO NPs exhibited a bactericidal effect, resulting in the eradication of 25% of the gram-negative bacteria E. coli and 32% of the gram-positive bacteria S. aureus. The antibacterial activity of NiO NPs has been attributed to the generation of ions that interact with thiol protein groups present in bacterial cells, resulting in their demise. This antibacterial activity is linked to oxygen species interactions, such as stress oxidation, hydrogen peroxide, hydroxyl, and superoxide. When the results were examined, it was found that the synthesized NiO NPs have more effective antibacterial activity against both gram-positive and gram-negative bacteria. Today, although it is reported that the chemicals available in the control of plant viruses have little or no effectiveness, studies on the development of alternative methods in agricultural control continue. In these studies, especially methods that offer nanotechnology-based solutions have become the center of attention. Based on this information, NiO nanostructures developed by Derbalah et al. showed efficacy against Cucumber mosaic virus (CMV) in cucumbers (Derbalah et al., 2019). In this study, the NiO nanostructures produced induced systemic resistance when applied to cucumbers and the ability to control the virus by showing antiviral activity directly against CMV was evaluated. Biologically, NiO nanostructures showed efficacy in reducing disease severity, CMV accumulation, and expression of regulatory and defense-related genes. When the plant groups treated and untreated with NiO nanostructures were compared, it was reported that (i) a significant suppression of CMV infection and reduction of its accumulation was detected by enzyme-linked immunosorbent assay (ELISA) and (ii) an increase in the expression of defense and regulatory genes related to salicylic acid and jasmonic acid/ethylene was detected by real-time polymerase chain reaction (RT-PCR) test in the treated groups. Based on these results, NiO nanostructures have been reported to have antiviral properties. This study is the first study in the literature to examine the effectiveness of NiO nanostructures on CMV. NiO nanostructures were composited with reduced graphene oxide (rGO) to be used in biosensor applications (Reddy et al., 2022). In this study, NiO nanostructures were used to improve the biosensing properties of rGO.  In addition, some recent studies have reported that NiO-based materials are used for electrochemical sensing and energy storage and are preferred due to their environmental stability (Ramu et al., 2021). This designed biosensor is defined as an ultra-sensitive peptidebased nano-biosensor designed to detect active influenza viruses H1N1 and H5N2

256

A. M. Allahverdiyev et al.

and viral proteins. In the tests, it was observed that synergistic signaling effects occur when viruses accumulate on the electrode together with electrical conductivity and porosity properties. Considering these observations, it is concluded that the developed nano-biosensor is sensitive and specific in detecting influenza viruses and viral proteins. In addition, it was stated that this biosensor could be useful in terms of creating a prediction in affected patients by using this biosensor in clinical screening tools.

Future Use Various studies have been conducted to investigate the antibacterial activities of NiO NPs. These NPs have shown strong antibacterial action against gram-positive and gram-negative bacteria. The mechanisms underpinning their antibacterial effect include ROS production within bacterial cells, Ni2+ release, and NP adsorption on cellular membranes. NiO NPs have been observed in bacteria to impair cell wall construction, depolarize cellular membranes, and impede nucleic acid and protein synthesis. NiO NPs have been shown to have antibacterial action against a variety of pathogenic bacteria, including S. pneumoniae, S. aureus, E. coli, and S. mutans. Antibacterial activity of NiO NPs rises with concentration, and they exhibit greater inhibition zones against gram-negative bacteria than gram-positive bacteria. This might be due to structural changes in cell walls and surface charges among various bacterial species. NiO NPs have been discovered to enter bacterial cell walls, disrupting cellular activity and respiration processes. The release of Ni2+ and the generation of ROS both contribute to antibacterial action by causing bacterial cell components to be damaged. The use of plant extracts in the synthesis of NiO NPs, such as Bergenia ciliate, Averrhoa bilimbi fruit, and Rhamnus prinoides leaf, provides an environmentally benign and cost-effective technique. These greenly produced NiO NPs have outstanding antibacterial characteristics and have shown promise for a variety of applications, including wastewater purification, bacterial growth inhibition, and free radical scavenging. Overall, the antibacterial effects of NiO NPs have been linked to their distinct physicochemical features, which include particle size, shape, concentration, and surface properties. When NiO NPs interact with bacterial cells, they cause cellular damage and death. NiO NPs show promise as a viable antibiotic alternative, with strong antibacterial activity and the ability to address the issue of antibiotic resistance in the biomedical and manufacturing industries. As far as examined in the literature, it is observed that there are few studies on the antiviral properties of NiO nanostructures. In future studies, NiO nanostructures can be combined with other materials that can support/improve each other and their antiviral activities can be investigated. Especially, the fact that metal and metal oxide NPs have antiviral activity and virus diagnostic potential suggests that NiO nanostructures should be investigated more widely in this field. For this reason, the use of NiO nanostructures in the detection of viruses can be expanded by incorporating their unique properties into biosensor designs.

NiO Nanoparticles for Advanced Clinical Applications

257

Conclusion In many studies, it has been revealed that NiO nanoparticles show a very strong antimicrobial activity. However, it is clear that there are some factors that determine the effectiveness of NiO nanoparticles. Size and shape are the most important of these factors. On the other hand, the method used in the synthesis of NiO nanoparticles is of great importance in increasing the bioavailability of these nanoparticles. Studies have shown that NiO nanoparticles produced by green synthesis method from extracts prepared using roots, stems, or leaves of different plants are much more efficient. Studies have shown that NiO nanoparticles obtained by green synthesis show much higher antimicrobial activity compared to nanoparticles obtained by chemical synthesis, and their biocompatibility is more suitable. We think that these parameters should be considered in the production of new-generation NiO nanoparticles. On the other hand, in the literature analysis, it is seen that the studies on the antibacterial activities of NiO nanoparticles are much more than the studies on the antiviral activities. Antibacterial action mechanisms of NiO nanoparticles, which are based on liberating Ni2+, producing reactive oxygen species or directly binding to nucleic acids, cell membranes, or protein structures of microorganisms, have been well elucidated to date. On the other hand, the mechanism of action of NiO nanoparticles on viruses is not very clear. No detailed research has been conducted to examine their effectiveness on SARS-CoV-2, which caused the COVID-19 pandemic. Studies have shown that the use of NiO nanoparticles in respiratory tract infections caused by viruses may not be very effective and safe due to the high uptake of NiO nanoparticles in the lungs and possible toxic effects. For this reason, it is argued that it is more advantageous to use NiO nanoparticles in the production of virus transmission masks and in the development of biosensors that can be used in the diagnosis of viruses. As a result, within the scope of this review, it has been revealed that the potential of NiO nanoparticles to be used in medical applications is extremely high due to their important properties. However, new studies are needed to minimize the toxicities of these nanoparticles and to make their use more reliable for clinical trials.

References Abudayyak, M., Güzel, E., & Özhan, G. (2020). Cytotoxic, genotoxic, and apoptotic effects of nickel oxide nanoparticles in intestinal epithelial cells. Turkish Journal of Pharmaceutical Sciences, 17(4), 446. https://doi.org/10.4274/TJPS.GALENOS.2019.76376 Ahghari, M. R., Soltaninejad, V., & Maleki, A. (2020). Synthesis of nickel nanoparticles by a green and convenient method as a magnetic mirror with antibacterial activities. Scientific Reports, 10(1), 1–10. https://doi.org/10.1038/s41598-­020-­69679-­4 Ahmed, A., Ahmed, S., Johari, R., Parvaz, M., & Rafat, M. (2019). Dual-energy application of NiO: Electrochemical and photovoltaic properties. Optik, 179, 485–491. https://doi.org/10.1016/J. IJLEO.2018.10.195

258

A. M. Allahverdiyev et al.

Ali, T., Warsi, M.  F., Zulfiqar, S., Sami, A., Ullah, S., Rasheed, A., Alsafari, I.  A., Agboola, P. O., Shakir, I., & Baig, M. M. (2022). Green nickel/nickel oxide nanoparticles for prospective antibacterial and environmental remediation applications. Ceramics International, 48(6), 8331–8340. https://doi.org/10.1016/J.CERAMINT.2021.12.039 Alkilany, A.  M., & Murphy, C.  J. (2010). Toxicity and cellular uptake of gold nanoparticles. Journal of Nanoárticle Research, 12, 2313–2333. https://doi.org/10.1007/s11051-­010-­9911-­8 Allahverdiyev, A. (2018). Somatik ve kök hücre kültür sistemlerinin temel ilkeleri. Nobel Tıp Kitabevi. Angel Ezhilarasi, A., Judith Vijaya, J., Kaviyarasu, K., John Kennedy, L., Ramalingam, R. J., & Al-Lohedan, H. A. (2018). Green synthesis of NiO nanoparticles using Aegle marmelos leaf extract for the evaluation of in-vitro cytotoxicity, antibacterial and photocatalytic properties. Journal of Photochemistry and Photobiology B: Biology, 180, 39–50. https://doi.org/10.1016/J. JPHOTOBIOL.2018.01.023 Auffan, M., Rose, J., Bottero, J. Y., Lowry, G. V., Jolivet, J. P., & Wiesner, M. R. (2009). Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nature Nanotechnology, 4(10), 634–641. https://doi.org/10.1038/nnano.2009.242 Ba-Abbad, M. M., Chai, P. V., Takriff, M. S., Benamor, A., & Mohammad, A. W. (2015). Optimization of nickel oxide nanoparticle synthesis through the sol-gel method using Box-Behnken design. Materials and Design, 86, 948–956. https://doi.org/10.1016/J.MATDES.2015.07.176 Barabadi, H., Ovais, M., Shinwari, Z. K., & Saravanan, M. (2017). Anti-cancer green bionanomaterials: Present status and future prospects. http://Mc.Manuscriptcentral.Com/Tgcl, 10(4), 285–314. https://doi.org/10.1080/17518253.2017.1385856 Bora, P. J., Vinoy, K. J., Ramamurthy, P. C., Kishore, & Madras, G. (2017). Electromagnetic interference shielding effectiveness of polyaniline-nickel oxide coated cenosphere composite film. Composites Communications, 4, 37–42. https://doi.org/10.1016/J.COCO.2017.04.002 Cao, Z., Fang, Y., Lu, Y., Qian, F., Ma, Q., He, M., Pi, H., Yu, Z., & Zhou, Z. (2016). Exposure to nickel oxide nanoparticles induces pulmonary inflammation through NLRP3 inflammasome activation in rats. International Journal of Nanomedicine, 11, 3331–3346. https://doi. org/10.2147/IJN.S106912 Chang, X., Zhao, H., Gao, J., Chen, L., Zhu, A., Wang, C., Yu, S., Ren, X., Ge, P., & Sun, Y. (2018). Pulmonary toxicity of exposure to nano nickel oxide. Micro and Nano Letters, 13(6), 733. https://doi.org/10.1049/mnl.2017.0802 Cho, W. S., Duffin, R., Bradley, M., Megson, I. L., MacNee, W., Howie, S. E. M., & Donaldson, K. (2012). NiO and Co3O4 nanoparticles induce lung DTH-like responses and alveolar lipoproteinosis. The European Respiratory Journal, 39(3), 546–557. https://doi. org/10.1183/09031936.00047111 Dadkhah, M., & Tulliani, J. M. (2022). Green synthesis of metal oxides semiconductors for gas sensing applications. Sensors, 22(13), 4669. https://doi.org/10.3390/S22134669 de Wang, Y., Ma, C. L., Sun, X. D., & Li, H. D. (2002). Preparation of nanocrystalline metal oxide powders with the surfactant-mediated method. Inorganic Chemistry Communications, 5(10), 751–755. https://doi.org/10.1016/S1387-­7003(02)00546-­4 Dehno Khalaji, A., Grivani, G., Izadi, S., & Ebadi, M. (2018). Facile synthesis of Ni/NiO nanocomposites via thermal decomposition. Journal of Nanoanalysis, 5(2), 115–122. https://doi. org/10.22034/JNA.2018.541868 Drummer, S., Madzimbamuto, T., & Chowdhury, M. (2021). Green synthesis of transition-metal nanoparticles and their oxides: A review. Materials, 14(11), 2700. https://doi.org/10.3390/ MA14112700/S1 Erman Salih Istifli., & Hasan Basri Ila. (2019). Cytotoxicity – definition, identification, and cytotoxic compounds. IntechOpen. Gebretinsae, H.  G., Tsegay, M.  G., & Nuru, Z.  Y. (2021). Biosynthesis of nickel oxide (NiO) nanoparticles from cactus plant extract, 566–570. https://doi.org/10.1016/j.matpr.2020.05.331

NiO Nanoparticles for Advanced Clinical Applications

259

Ghosal, A., Iqbal, S., & Ahmad, S. (2019). NiO nanofiller dispersed hybrid Soy epoxy anticorrosive coatings. Progress in Organic Coatings, 133, 61–76. https://doi.org/10.1016/J. PORGCOAT.2019.04.029 Gupta, V., Kant, V., Gupta, A., & Sharma, M. (2020). Synthesis, characterization and concentration dependant antibacterial potentials of nickel oxide nanoparticles against Staphylococcus aureus and Escherichia coli. Nanosystems: Physics, Chemistry, Mathematics, 11(2), 237–245. https:// doi.org/10.17586/2220-­8054-­2020-­11-­2-­237-­245 Habtemariam, A.  B., & Bekele, E. (2022). Facile synthesis of nickel oxide nanoparticles using Rhamnus prinoides leaf extract and evaluation of its antibacterial activities. Regenerative Engineering and Translational Medicine, 8(3), 482–488. https://doi.org/10.1007/ S40883-­022-­00251-­4 Hamed Derbalah, A. S., & Elsharkawy, M. M. (2019). A new strategy to control cucumber mosaic virus using fabricated NiO-nanostructures. Journal of Biotechnology, 306, 134–141. https:// doi.org/10.1016/J.JBIOTEC.2019.10.003 Haritha, V., Gowri, S., Janarthanan, B., Faiyazuddin, M., Karthikeyan, C., & Sharmila, S. (2022). Biogenic synthesis of nickel oxide nanoparticles using Averrhoa bilimbi and investigation of its antibacterial, antidiabetic and cytotoxic properties. Inorganic Chemistry Communications, 144, 109930. https://doi.org/10.1016/J.INOCHE.2022.109930 Helan, V., Prince, J. J., Al-Dhabi, N. A., Arasu, M. V., Ayeshamariam, A., Madhumitha, G., Roopan, S. M., & Jayachandran, M. (2016). Neem leaves mediated preparation of NiO nanoparticles and its magnetization, coercivity and antibacterial analysis. Results in Physics, 6, 712–718. https://doi.org/10.1016/J.RINP.2016.10.005 Huang, J., Lin, L., Sun, D., Chen, H., Yang, D., & Li, Q. (2015). Bio-inspired synthesis of metal nanomaterials and applications. Chemical Society Reviews, 44(17), 6330–6374. https://doi. org/10.1039/C5CS00133A Idris, A. O., Mafa, P. J., Oseghe, E. O., Msagati, T. A. M., Feleni, U., & Mamba, B. B. (2021). A facile approach for the preparation of NiONPs@MnO2NRs nanocomposite material and its photocatalytic activity. Journal of Nanoparticle Research, 23(7), 1–14. https://doi.org/10.1007/ S11051-­021-­05257-­7/FIGURES/9 Imran Din, M., & Rani, A. (2016). Recent advances in the synthesis and stabilization of nickel and nickel oxide nanoparticles: A green adeptness. International Journal of Analytical Chemistry., 2016, 1. https://doi.org/10.1155/2016/3512145 Jafari, A., Pilban Jahromi, S., Boustani, K., Goh, B.  T., & Huang, N.  M. (2019). Evolution of structural and magnetic properties of nickel oxide nanoparticles: Influence of annealing ambient and temperature. Journal of Magnetism and Magnetic Materials, 469, 383–390. https://doi. org/10.1016/J.JMMM.2018.08.005 Jaji, N. D., Lee, H. L., Hussin, M. H., Akil, H. M., Zakaria, M. R., & Othman, M. B. H. (2020). Advanced nickel nanoparticles technology: From synthesis to applications. Nanotechnology Reviews, 9(1), 1456–1480. https://doi.org/10.1515/NTREV-­2020-­0109/ASSET/GRAPHIC/J_ NTREV-­2020-­0109_FIG_005.JPG Kalita, C., & Saikia, P. (2021). Magnetically separable tea leaf mediated nickel oxide nanoparticles for excellent photocatalytic activity. Journal of the Indian Chemical Society, 98(11), 100213. https://doi.org/10.1016/J.JICS.2021.100213 Kannan, K., Radhika, D., Nikolova, M.  P., Sadasivuni, K.  K., Mahdizadeh, H., & Verma, U. (2020). Structural studies of bio-mediated NiO nanoparticles for photocatalytic and antibacterial activities. Inorganic Chemistry Communications, 113, 107755. https://doi.org/10.1016/J. INOCHE.2019.107755 Khan, I., Saeed, K., & Khan, I. (2019). Nanoparticles: Properties, applications and toxicities. Arabian Journal of Chemistry, 12(7), 908–931. https://doi.org/10.1016/J.ARABJC.2017.05.011 Khashan, K. S., Sulaiman, G. M., Hamad, A. H., Abdulameer, F. A., & Hadi, A. (2017). Generation of NiO nanoparticles via pulsed laser ablation in deionised water and their antibacterial activity. Applied Physics A: Materials Science and Processing, 123(3), 1–10. https://doi.org/10.1007/ S00339-­017-­0826-­4/TABLES/2

260

A. M. Allahverdiyev et al.

Khodair, Z. T., Ibrahim, N. M., Kadhim, T. J., & Mohammad, A. M. (2022). Synthesis and characterization of nickel oxide (NiO) nanoparticles using an environmentally friendly method, and their biomedical applications. Chemical Physics Letters, 797, 139564. https://doi. org/10.1016/J.CPLETT.2022.139564 Lee, S. B., Lee, J., Tsang, Y. F., Kim, Y. M., Jae, J., Jung, S. C., & Park, Y. K. (2021). Production of value-added aromatics from wasted COVID-19 mask via catalytic pyrolysis. Environmental Pollution (Barking, Essex: 1987), 283. https://doi.org/10.1016/J.ENVPOL.2021.117060 Legmairi, S., Meneceur, S., Bouafia, A., Laouini, S. E., Alshareef, S. A., Al-Essa, K., Almukhlifi, H. A., Tedjani, M. L., & Menaa, F. (2023). Biofabrication of NiO and NiO-decorated Fe nanocomposite efficiency for removal of methylene blue from aqueous solution. Biomass Conversion and Biorefinery, 1, 1–11. https://doi.org/10.1007/S13399-­023-­03912-­8/FIGURES/8 Li, G., Ma, M., Chen, X., Zhang, J., Hong, Y., Huan, Y., & Wei, T. (2023). Nickel-ion activating discarded COVID-19 medical surgical masks for forming carbon-nickel composite nanowires and using as a high-performance lithium battery anode. Energy and Fuels, 37(1), 702. https:// doi.org/10.1021/acs.energyfuels.2c03129 Likasari, I. D., Astuti, R. W., Yahya, A., Isnaini, N., Purwiandono, G., Hidayat, H., Wicaksono, W.  P., & Fatimah, I. (2021). NiO nanoparticles synthesized by using Tagetes erecta L leaf extract and their activities for photocatalysis, electrochemical sensing, and antibacterial features. Chemical Physics Letters, 780, 138914. https://doi.org/10.1016/J.CPLETT.2021.138914 Lingaraju, K., Raja Naika, H., Nagabhushana, H., Jayanna, K., Devaraja, S., & Nagaraju, G. (2020). Biosynthesis of nickel oxide nanoparticles from Euphorbia heterophylla (L.) and their biological application. Arabian Journal of Chemistry, 13(3), 4712–4719. https://doi.org/10.1016/J. ARABJC.2019.11.003 Llop, J., Estrela-Lopis, I., Ziolo, R. F., González, A., Fleddermann, J., Dorn, M., Vallejo, V. G., Simon-Vazquez, R., Donath, E., Mao, Z., Gao, C., & Moya, S. E. (2014). Uptake, biological fate, and toxicity of metal oxide nanoparticles. Particle & Particle Systems Characterization, 31(1), 24–35. https://doi.org/10.1002/PPSC.201300323 Lu, S., Zhang, W., Zhang, R., Liu, P., Wang, Q., Shang, Y., Wu, M., Donaldson, K., & Wang, Q. (2015). Comparison of cellular toxicity caused by ambient ultrafine particles and engineered metal oxide nanoparticles. Particle and Fibre Toxicology, 12(1), 1–12. https://doi.org/10.1186/ S12989-­015-­0082-­8/FIGURES/8 Makarov, V. V., Love, A. J., Sinitsyna, O. V., Makarova, S. S., Yaminsky, I. V., Taliansky, M. E., & Kalinina, N. O. (2014). “Green” nanotechnologies: Synthesis of metal nanoparticles using plants. Acta Naturae, 6(1), 35. https://doi.org/10.32607/20758251-­2014-­6-­1-­35-­44 Mala, N. A., Dar, M. A., Sivakumar, S., Dar, T. A., & Manikandan, E. (2022). Review article on the performance of electrochemical capacitors when altered metals doped with nickel oxide nanomaterials. Journal of Nanoparticle Research, 24(11), 1–17. https://doi.org/10.1007/ S11051-­022-­05605-­1/FIGURES/8 Manohara Reddy, Y. V., Shin, J. H., Hwang, J., Kweon, D. H., Choi, C. H., Park, K., Kim, S. K., Madhavi, G., Yi, H., & Park, J. P. (2022). Fine-tuning of MXene-nickel oxide-reduced graphene oxide nanocomposite bioelectrode: Sensor for the detection of influenza virus and viral protein. Biosensors and Bioelectronics, 214, 114511. https://doi.org/10.1016/J.BIOS.2022.114511 Martín-Camacho, U. J., Torres-Ramos, M. I., Sánchez-Burgos, J. A., & Pérez-Larios, A. (2022). Drug delivery system of green synthesized Ti-Cu nanocomposite. Materials Letters, 321, 132437. https://doi.org/10.1016/J.MATLET.2022.132437 Mirza, A. U., Khan, M. S., Kareem, A., Nami, S. A. A., Bhat, S. A., Mohammad, A., Singh, P., & Nishat, N. (2021). Biomediated synthesis, characterization, and biological applications of nickel oxide nanoparticles derived from Toona ciliata, Ficus carica and Pinus r­ oxburghii. Bioprocess and Biosystems Engineering, 44(7), 1461–1476. https://doi.org/10.1007/S00449-­021-­02528-­4 Mohammadi, E., Aliofkhazraei, M., Hasanpoor, M., & Chipara, M. (2018). Hierarchical and complex ZnO nanostructures by microwave-assisted synthesis: Morphologies, growth mechanism and classification. Critical Reviews in Solid State and Materials Sciences, 43(6), 475–541. https://doi.org/10.1080/10408436.2017.1397501

NiO Nanoparticles for Advanced Clinical Applications

261

Murthy, S. K. (2007). Nanoparticles in modern medicine: State of the art and future challenges. International Journal of Nanomedicine, 2(2), 129. /pmc/articles/PMC2673971/. Narender, S.  S., Varma, V.  V. S., Srikar, C.  S., Ruchitha, J., Varma, P.  A., & Praveen, B.  V. S. (2022). Nickel oxide nanoparticles: A brief review of their synthesis, characterization, and applications. Chemical Engineering & Technology, 45(3), 397–409. https://doi. org/10.1002/CEAT.202100442 Nath, A., Das, A., Deb, S., Bhattacharjee, C. R., & Rout, J. (2016). Green synthesis of novel antioxidant luminescent silica nanoparticle embedded carbon nanocomposites from a blue-green alga. Green Processing and Synthesis, 5(2), 189–194. https://doi.org/10.1515/GPS-­2015-­0124/ MACHINEREADABLECITATION/RIS Nazaripour, E., Mosazadeh, F., Rahimi, S.  S., Alijani, H.  Q., Isaei, E., Borhani, F., Iravani, S., Ghasemi, M., Akbarizadeh, M.  R., Azizi, E., Sharifi, F., Haghighat, M., Hadizadeh, S., Moghadam, M. D., Abdollahpour-Alitappeh, M., & Khatami, M. (2022). Ferromagnetic nickel (II) oxide (NiO) nanoparticles: Biosynthesis, characterization and their antibacterial activities. Rendiconti Lincei, 33, 127. https://doi.org/10.1007/S12210-­021-­01042-­9 Nguyen, D.  H., Lee, J.  S., Park, K.  D., Ching, Y.  C., Nguyen, X.  T., Phan, V.  H. G., & Thi, T.  T. H. (2020). Green silver nanoparticles formed by Phyllanthus urinaria, Pouzolzia zeylanica, and Scoparia dulcis leaf extracts and the antifungal activity. Nanomaterials, 10(3), 542. https://doi.org/10.3390/NANO10030542 Nikolova, M. P., & Chavali, M. S. (2020). Metal Oxide Nanoparticles as Biomedical Materials. Biomimetics, 5(2), 27. https://doi.org/10.3390/BIOMIMETICS5020027 Oyabu, T., Myojo, T., Lee, B.  W., Okada, T., Izumi, H., Yoshiura, Y., Tomonaga, T., Li, Y.  S., Kawai, K., Shimada, M., Kubo, M., Yamamoto, K., Kawaguchi, K., Sasaki, T., & Morimoto, Y. (2017). Biopersistence of NiO and TiO2 nanoparticles following intratracheal instillation and inhalation. International Journal of Molecular Sciences, 18(12). https://doi.org/10.3390/ ijms18122757 Pan, Y., Du, X., Zhao, F., & Xu, B. (2012). Magnetic nanoparticles for the manipulation of proteins and cells. Chemical Society Reviews, 41(7), 2912–2942. https://doi.org/10.1039/C2CS15315G Peng, X., Palma, S., Fisher, N. S., & Wong, S. S. (2011). Effect of morphology of ZnO nanostructures on their toxicity to marine algae. Aquatic Toxicology, 102(3–4), 186–196. https://doi. org/10.1016/J.AQUATOX.2011.01.014 Prabhu, S., Daniel Thangadurai, T., Vijai Bharathy, P., & Kalugasalam, P. (2022). Synthesis and characterization of nickel oxide nanoparticles using Clitoria ternatea flower extract: Photocatalytic dye degradation under sunlight and antibacterial activity applications. Results in Chemistry, 4, 100285. https://doi.org/10.1016/J.RECHEM.2022.100285 Rajith Kumar, C. R., Betageri, V. S., Nagaraju, G., Pujar, G. H., Suma, B. P., & Latha, M. S. (2020). Photocatalytic, nitrite sensing and antibacterial studies of facile bio-synthesized nickel oxide nanoparticles. Journal of Science: Advanced Materials and Devices, 5(1), 48–55. https://doi. org/10.1016/J.JSAMD.2020.02.002 Ramu, A. G., Umar, A., Ibrahim, A. A., Algadi, H., Ibrahim, Y. S. A., Wang, Y., Hanafiah, M. M., Shanmugam, P., & Choi, D. (2021). Synthesis of porous 2D layered nickel oxide-reduced graphene oxide (NiO-rGO) hybrid composite for the efficient electrochemical detection of epinephrine in biological fluid. Environmental Research, 200, 111366. https://doi.org/10.1016/J. ENVRES.2021.111366 Rehman, F.  U., Mahmood, R., Ali, M.  B., Hedfi, A., Mezni, A., Haq, S., Din, S.  U., & Ehsan, R. (2021). Physicochemical, photocatalytic, antibacterial, and antioxidant screening of bergenia ciliata mediated nickel oxide nanoparticles. Crystals, 11(9). https://doi.org/10.3390/ CRYST11091137 Renuka, R., Renuka Devi, K., Sivakami, M., & Thilagavathi, T. (2021). Solanum torvum mediated synthesis and characterization of silver nanoparticles for antibacterial activities. Journal of Plant Biochemistry and Biotechnology, 30(3), 596–601. https://doi.org/10.1007/ S13562-­021-­00650-­8

262

A. M. Allahverdiyev et al.

Sabouri, Z., Akbari, A., Hosseini, H. A., Hashemzadeh, A., & Darroudi, M. (2019). Eco-friendly biosynthesis of nickel oxide nanoparticles mediated by okra plant extract and investigation of their photocatalytic, magnetic, cytotoxicity, and antibacterial properties. Journal of Cluster Science, 30(6), 1425–1434. https://doi.org/10.1007/S10876-­019-­01584-­X/FIGURES/12 Sabouri, Z., Akbari, A., Hosseini, H. A., Khatami, M., & Darroudi, M. (2020). Egg white-mediated green synthesis of NiO nanoparticles and study of their cytotoxicity and photocatalytic activity. Polyhedron, 178, 114351. https://doi.org/10.1016/J.POLY.2020.114351 Saheb, M., Hosseini, H.  A., Hashemzadeh, A., Elahi, B., Hasanzadeh, L., Oskuee, R.  K., & Darroudi, M. (2019). Photocatalytic and biological attributes of green synthesized nickel oxide nanoparticles by Rheum Turkestanicum (RT) root extract. ChemistrySelect, 4(8), 2416–2420. https://doi.org/10.1002/SLCT.201803903 Sahoo, B.  B., Pandey, V.  S., Dogonchi, A.  S., Mohapatra, P.  K., Thatoi, D.  N., Nayak, N., & Nayak, M. K. (2023). A state-of-art review on 2D material-boosted metal oxide nanoparticle electrodes: Supercapacitor applications. Journal of Energy Storage, 65, 107335. https://doi. org/10.1016/J.EST.2023.107335 Salem, S. S. (2023). A mini review on green nanotechnology and its development in biological effects. Archives of Microbiology, 205(4), 1–15. https://doi.org/10.1007/S00203-­023-­03467-­2 Sana, S.  S., Singh, R.  P., Sharma, M., Srivastava, A.  K., Manchanda, G., Rai, A.  R., & Zhang, Z.-J. (2021). Biogenesis and application of nickel nanoparticles: A review. Current Pharmaceutical Biotechnology, 22(6), 808–822. https://doi.org/10.217 4/1389201022999210101235233 Sarkar, N., Sharma, R. S., & Kaushik, M. (2020). Green synthesis and physiochemical characterization of nickel oxide nanoparticles: Interaction studies with Calf thymus DNA. Luminescence, 35(2), 178–186. https://doi.org/10.1002/BIO.3709 Shanan, Z. J., & Shanshool, S. K. (2023). Nickel oxide nanoparticles: Synthesis and evaluation for antimicrobial efficacy. International Journal of Nanoscience, 22. https://doi.org/10.1142/ S0219581X23500084 Shnawa, B.  H., Jalil, P.  J., Hamad, S.  M., & Ahmed, M.  H. (2022). Antioxidant, protoscolicidal, hemocompatibility, and antibacterial activity of nickel oxide nanoparticles synthesized by Ziziphus spina-christi. BioNanoScience, 12(4), 1264–1278. https://doi.org/10.1007/ S12668-­022-­01028-­3 Shwetha, U.  R., Rajith Kumar, C.  R., Kiran, M.  S., Betageri, V.  S., Latha, M.  S., Veerapur, R., Lamraoui, G., Al-Kheraif, A.  A., Elgorban, A.  M., Syed, A., Shivamallu, C., & Kollur, S.  P. (2021). Biogenic synthesis of NiO nanoparticles using Areca catechu leaf extract and their antidiabetic and cytotoxic effects. Molecules (Basel, Switzerland), 26(9). https://doi. org/10.3390/MOLECULES26092448 Siddiqui, M. A., Ahamed, M., Ahmad, J., Majeed Khan, M. A., Musarrat, J., Al-Khedhairy, A. A., & Alrokayan, S.  A. (2012). Nickel oxide nanoparticles induce cytotoxicity, oxidative stress and apoptosis in cultured human cells that is abrogated by the dietary antioxidant curcumin. Food and Chemical Toxicology, 50(3–4), 641–647. https://doi.org/10.1016/J.FCT.2012.01.017 Soltys, L., Olkhovyy, O., Tatarchuk, T., & Naushad, M. (2021). Green synthesis of metal and metal oxide nanoparticles: Principles of green chemistry and raw materials. Magnetochemistry, 7(11), 145. https://doi.org/10.3390/MAGNETOCHEMISTRY7110145 Stoddart, M. J. (2011). Cell viability assays: Introduction. Methods in Molecular Biology (Clifton, N.J.), 740, 1–6. https://doi.org/10.1007/978-­1-­61779-­108-­6_1 Suresh, S., Karthikeyan, S., Saravanan, P., & Jayamoorthy, K. (2016). Comparison of antibacterial and antifungal activities of 5-amino-2-mercaptobenzimidazole and functionalized NiO nanoparticles. Karbala International Journal of Modern Science, 2(3), 188–195. https://doi. org/10.1016/J.KIJOMS.2016.05.001 Thanh, N.  T. K., Maclean, N., & Mahiddine, S. (2014). Mechanisms of nucleation and growth of nanoparticles in solution. Chemical Reviews, 114(15), 7610–7630. https://doi.org/10.1021/ CR400544S/ASSET/IMAGES/MEDIUM/CR-­2013-­00544S_0032.GIF

NiO Nanoparticles for Advanced Clinical Applications

263

Thirbika, S., Karthi, H., Premila, R., & Ramesh Prabhu, M. (2022). Investigations on biosynthesized nickel oxide nanoparticles using Cymbopogon citratus leaf extract for antibacterial activity. Materials Today: Proceedings, 68, 276–281. https://doi.org/10.1016/J.MATPR.2022.05.168 Uddin, S., Safdar, L.  B., Iqbal, J., Yaseen, T., Laila, S., Anwar, S., Abbasi, B.  A., Saif, M.  S., & Quraishi, U.  M. (2021). Green synthesis of nickel oxide nanoparticles using leaf extract of Berberis balochistanica: Characterization, and diverse biological applications. Microscopy Research and Technique, 84(9), 2004–2016. https://doi.org/10.1002/JEMT.23756 Ullah, M. W., Manan, S., Khattak, W. A., Shahzad, A., Ul-Islam, M., & Yang, G. (2020). Biotemplate-­ mediated green synthesis and applications of nanomaterials. Current Pharmaceutical Design, 26(45), 5819–5836. https://doi.org/10.2174/1381612824999201105164531 Veranth, J. M., Kaser, E. G., Veranth, M. M., Koch, M., & Yost, G. S. (2007). Cytokine responses of human lung cells (BEAS-2B) treated with micron-sized and nanoparticles of metal oxides compared to soil dusts. Particle and Fibre Toxicology, 4, 2. https://doi.org/10.1186/1743-8977-4-2 Vijaya Kumar, P., Jafar Ahamed, A., & Karthikeyan, M. (2019). Synthesis and characterization of NiO nanoparticles by chemical as well as green routes and their comparisons with respect to cytotoxic effect and toxicity studies in microbial and MCF-7 cancer cell models. SN Applied Sciences, 1(9), 1–15. https://doi.org/10.1007/S42452-­019-­1113-­0/FIGURES/13 Zarenezhad, E., Abdulabbas, H. T., Marzi, M., Ghazy, E., Ekrahi, M., Pezeshki, B., Ghasemian, A., & Moawad, A. A. (2022). Nickel nanoparticles: Applications and antimicrobial role against methicillin-resistant Staphylococcus aureus infections. Antibiotics, 11(9), 1208. https://doi. org/10.3390/ANTIBIOTICS11091208 Zhang, Q., Xu, S., Li, Y., Ding, P., Zhang, Y., & Zhao, P. (2021). Green-synthesized nickel oxide nanoparticles enhances biohydrogen production of Klebsiella sp. WL1316 using lignocellulosic hydrolysate and its regulatory mechanism. Fuel, 305, 121585. https://doi.org/10.1016/j. fuel.2021.121585

Aluminum Oxide Nanoparticles: Properties and Applications Overview Rodrigo Cáceres Congreve, Carolina Paz Quezada, and Varaprasad Kokkarachedu

Overview Aluminum oxide nanoparticles (Al2O3 NPs), also known as alumina nanoparticles (Al-NPs), have garnered significant attention to various scientific and industrial domains due to their advanced bio/physicochemical properties. These particles possess a small size (1–100 nm) and a large surface area-to-volume ratio, making them attractive for a wide range of applications (Fig. 1) (Said et al., 2020a, b). Al2O3 NPs typically have a crystal structure known as corundum, which is the same structure as natural gemstones like sapphires and rubies. Their remarkable features include high hardness, thermal stability, electrical insulation, chemical inertness, and corrosion resistance, making them valuable in numerous areas (Förster, 2020). These nanoparticles can be synthesized through various methods, including the green process, sol-gel synthesis, precipitation, and thermal decomposition of precursor compounds. All of these methods allow control over the particle size, shape, and surface properties, facilitating tailored nanoparticles for specific applications (Said et al., 2020a, b). In the field of catalysis, Al2O3 NPs serve as efficient catalyst supports, enhancing reaction rates and selectivity. Additionally, their remarkable dielectric properties make them valuable for electronic and optoelectronic devices. Al2O3 NPs have demonstrated great promise in biomedical applications, including drug delivery systems, biomedical imaging, biosensing, and tissue engineering. Recent studies highlight their potent antimicrobial and antiviral properties, owing to R. C. Congreve · C. P. Quezada Departamento de Química Ambiental, Facultad de Ciencias, Universidad Católica de la Santísima Concepción, Concepción, Chile V. Kokkarachedu (*) Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_12

265

266

R. C. Congreve et al.

Fig. 1 (a) SEM image of aluminum oxide nanoparticle (Piriyawong et al., 2012), (b) TEM image of Al2O2 (Balasubramanyam et al., 2010), and (c) molecular structure of aluminum oxide

their small size that enables effective penetration into bacterial and viral cells, increasing their efficacy (Manikandan et al., 2019). In the context of medical devices and hospital surfaces, Al2O3 NPs can be incorporated into coatings to prevent bacterial adhesion and biofilm formation, reducing the risk of infections. Additionally, throughout history, these nanoparticles have shown potent adjuvant activity in vaccines, effectively targeting and neutralizing a wide range of microorganisms. This characteristic enhances the efficacy of vaccines in generating robust immune responses. As a material of the future, Al2O3 NPs hold great promise as key components in advanced coatings, energy storage systems, catalysis, biomedical applications, environmental remediation, optoelectronics, photonics, and personal care products. However, the safety considerations are important when working with Al2O3 nanoparticles (NPs), and further research is ongoing to understand their potential toxicological effects. Proper precautions and adherence to safety guidelines are necessary when handling these nanomaterials (Martin et al., 2023).

Synthesis Methods for Al2O3 NPs Sol-Gel Method  In this technique, a precursor solution containing aluminum compounds are hydrolyzed and condensed to form a gel. The gel is then dried and calcined to obtain Al2O3 NPs (Bokov et al., 2021). This technique allows for precise control over the particle size, shape, and surface chemistry of the resulting Al2O3 NPs. It also offers a relatively low-temperature synthesis route, making it an energy-­ efficient process. Additionally, the sol-gel method can be easily scaled up for large-­ scale production. Green synthesis methods have also been developed for this technique, using environmentally friendly solvents and precursors. Hydrothermal Method  Aluminum hydroxides or salts are reacted in an aqueous solution at high temperature and pressure to form aluminum NPs (S O Kazantsev et al., 2018). This method produces highly crystalline Al2O3 NPs with a narrow size distribution. The high temperature and pressure conditions enable the formation of nanoparticles with a high degree of crystallinity, which is important for applica-

Aluminum Oxide Nanoparticles: Properties and Applications Overview

267

tions, such as catalysis and electronics. The hydrothermal method is also a simple and efficient synthesis route, making it a popular choice for industrial-scale production. Combustion Method  A combustion process involving the exothermic reaction between fuel and oxidizer is utilized to produce Al2O3 NPs (Nasiri et al., 2012). This method is a rapid and cost-effective synthesis route that can produce Al2O3 NPs with high purity and crystallinity. It offers advantages, such as a short reaction time, low cost, and simplicity of operation. Additionally, the combustion method can be used to synthesize doped or composite Al2O3 NPs by introducing dopant or precursor materials into the reaction mixture. Green combustion synthesis methods have also been developed, using bio-based fuels or green oxidizers to reduce the environmental impact of the process. Green or Biogenic Process  Biogenic processes for the synthesis of Al2O3 nanoparticles involve the use of biological agents such as bacteria, fungi, and plants to facilitate the formation of nanoparticles (Manikandan et al., 2019). These processes are gaining increasing attention due to their eco-friendliness, low cost, and potential for large-scale production. One advantage of biogenic Al2O3 NPs are their biocompatibility, which makes them suitable for use in biomedical applications. Biogenic synthesis methods can produce nanoparticles with a high degree of purity and crystallinity, which is important for biomedical applications, such as drug delivery, tissue engineering, and biosensing. Another advantage is that biogenic synthesis methods can produce nanoparticles with unique surface chemistries that can be tailored for specific biomedical applications. For example, surface functionalization of biogenic Al2O3 NPs with biomolecules, such as proteins or antibodies, can enhance their targeting and binding to specific cells or tissues. Biogenic Al2O3 NPs have also demonstrated promising antimicrobial properties, making them a potential candidate for use in antimicrobial coatings and wound dressings. Additionally, they have been shown to have low toxicity and can be easily eliminated from the body, reducing the risk of long-term health effects. Overall, these synthesis methods offer unique advantages for producing Al2O3 NPs with tailored properties for specific applications. The development of green synthesis methods have also contributed to reducing the environmental impact of nanoparticle production.

Physicochemical Properties of Al2O3 Aluminum oxide (Al2O3) is a versatile and important material with a range of physical and chemical properties that make it highly valuable for various applications. Figure 2 summarizes the main properties of these nanoparticles. Let us explore each of these properties in more detail:

268

R. C. Congreve et al.

Fig. 2  Main properties of Al2O2 NPs

High Thermal Stability  Aluminum oxide nanoparticles exhibit remarkable thermal stability, enabling them to withstand extreme temperatures without undergoing significant changes in their structure or properties. This characteristic makes them particularly useful in applications requiring heat resistance, such as the following: Heat-Resistant Coatings: Al2O3 nanoparticles can be incorporated into coatings to protect surfaces from high-temperature environments, such as those found in industrial equipment, engines, and exhaust systems. Refractory Materials: Al2O3 NPs are used in the production of refractories, which are materials that can withstand very high temperatures and are essential in industries like steel, glass, and cement manufacturing. High-Temperature Catalysts: The stability of Al2O3 nanoparticles makes them suitable as catalyst support materials for high-temperature reactions, where they provide a stable and durable platform for catalytic processes. Excellent Hardness  Due to their unique crystal structure, Al2O3 NPs possess high hardness, making them extremely resistant to mechanical wear and abrasion. This property allows for their application in various wear-resistant and cutting-edge technologies: Abrasive Materials: Al2O3 NPs are used as abrasives in grinding and polishing applications, where their hardness enables efficient material removal and surface finishing. Cutting Tools: Al2O3 NPs are incorporated into cutting tools, such as drill bits and saw blades, to improve their durability and extend their lifespan during cutting operations.

Aluminum Oxide Nanoparticles: Properties and Applications Overview

269

Wear-Resistant Coatings: Al2O3 NPs can be used to reinforce coatings on various surfaces, enhancing their wear resistance and longevity. Electrical Insulation Properties: Al2O3 NPs have low electrical conductivity, which makes them ideal for use in electronic devices and applications where electrical insulation is critical. Insulating Layers in Electronic Devices: Al2O3 NPs can be used to create thin insulating layers, such as gate dielectrics in transistors or insulating films in microelectronics, to prevent electrical leakage and improve device performance. Capacitors and Insulators: Al2O3 NPs are employed in the production of capacitors and insulating materials for electrical components. Surface Modification: The surface of Al2O3 NPs are highly amenable to modification, allowing for functionalization with various groups or coatings to tailor their properties for specific applications. Enhanced Stability and Dispersibility: Surface modifications can improve the stability and dispersibility of Al2O3 NPs in different solvents, making them more compatible with specific formulations and enhancing their performance in various applications. Specific Interactions with Target Molecules: By attaching specific functional groups to the nanoparticle surface, Al2O3 NPs can be tailored to interact with target molecules in applications like drug delivery, sensors, and catalysts (Mohammed et al., 2020). Overall, the combination of high thermal stability, excellent hardness, electrical insulation properties, and the ability for surface modification makes Al2O3 NPs a valuable material for a wide range of industries, including electronics, aerospace, automotive, energy, and healthcare, among others. Continued research and development in nanotechnology will likely unlock even more potential applications for Al2O3 NPs in the future. Applications Catalysis: These nanoparticles have a high surface area and can serve as catalysts or catalyst supports. They provide an increased number of active sites for reactions and can enhance catalytic efficiency. They find applications in diverse catalytic processes, such as hydrogenation, oxidation, and photocatalysis (Daroughegi et al., 2019). Nanoelectronics: Al2O3 NPs are used as dielectric materials or insulating layers in nanoelectronic devices, such as transistors and capacitors (Chavali et al., 2019). They exhibit a high dielectric constant, which enables the miniaturization of electronic components and enhances their performance. Al2O3 also possesses low leakage current and good interface properties with semiconductors, ensuring efficient device operation (Baek et al., 2016). Biomedical Applications: These nanoparticles can be used in different biomedical applications, including drug delivery, bioimaging, and tissue engineering. Due to their biocompatibility, they can serve as carriers for drugs, genes, or therapeutic agents, enabling controlled and targeted release (Harish et al., 2022). Al2O3 NPs can also be functionalized with specific biomolecules (e.g., antibodies) to achieve targeted drug delivery, or to enhance imaging contrast. In tissue engineering, it can be incorporated into scaffolds to improve mechanical properties and promote cell adhesion and growth (Fawcett et al., 2011).

270

R. C. Congreve et al.

Advantages and Disadvantages Advantages of Al2O3 Nanoparticles High Hardness and Mechanical Strength They possess high hardness, making them suitable for applications requiring strong and durable materials. Their mechanical strength allows them to withstand external forces and resist wear, making them useful in coatings, composites, and structural materials (Leung et al., 2014). These nanoparticles exhibit high strength and mechanical stability, which enables them to withstand external forces and maintain their structural integrity. Their robust nature makes them ideal for applications where materials need to withstand heavy loads, mechanical stress, and wear (Shah et  al., 2022). Due to their high hardness, Al2O3 NPs offer excellent resistance to wear and abrasion. When incorporated into coatings or composite materials, they can enhance the durability and lifespan of the substrate by providing a protective layer that can withstand friction and mechanical damage (Riquelme et al., 2022). Al2O3 NPs can be incorporated into various composite materials to enhance their strength and mechanical properties. When dispersed within a matrix material, such as polymers or metals, they reinforce the composite structure, improving its stiffness, tensile strength, and impact resistance. This makes them suitable for applications in aerospace, automotive, and construction industries where lightweight yet strong materials are used (Girimurugan et al., 2023). Excellent Thermal Stability These nanoparticles exhibit exceptional thermal stability, enabling them to withstand high temperatures without significant degradation. This property makes them valuable in high-temperature applications such as thermal barrier coatings, catalyst supports, and heat exchangers (Ramírez et  al., 2019). They provide a stable and inert platform for catalytic reactions that require high temperatures. The thermal stability of Al-NPs allows them to maintain their structure and surface properties, ensuring the stability and activity of supported catalysts (Beaton et al., 2022). Al2O3 is utilized in nanofluids for heat exchangers. The exceptional thermal stability allows them to maintain their dispersed state and thermal conductivity properties even at elevated temperatures. This enables efficient heat transfer and enhanced thermal performance in heat exchange applications (Lee et al., 2008). Chemical Inertness and Corrosion Resistance Al-NPs are chemically inert and resistant to corrosion. They do not readily react with various chemicals, acids, or alkalis, making them suitable for their use in corrosive environments. This property is advantageous in applications, such as coatings, catalysts, and protective layers (Niroumandrad et  al., 2016). The chemical inertness and resistance to corrosion of these nanoparticles make them suitable as catalysts in various chemical processes, including hydrogen production. Their stability allows them to withstand harsh reaction conditions and corrosive environments, maintaining their catalytic activity over extended periods (Khan et al., 2022). Al2O3 NPs are commonly used in protective coatings to enhance corrosion

Aluminum Oxide Nanoparticles: Properties and Applications Overview

271

resistance. These coatings can be applied through techniques such as electrodeposition, forming a chemically inert and corrosion-resistant layer that shields the underlying material from aggressive environments (Pirhady et al., 2021). Large Surface Area-to-Volume Ratio Due to their nanoscale dimensions, they have a significantly larger surface area-­ to-­volume ratio compared to their bulk counterparts. This increased surface area allows for enhanced interactions with other substances, leading to improved reactivity and performance in applications such as catalysis, adsorption, and sensors (Altammar, 2023). With a large surface area-to-volume ratio, they exhibit enhanced catalytic activity. The increased surface area provides more active sites for catalytic reactions, allowing for improved reaction efficiency and selectivity in various catalytic processes (Hameed & Muralidharan, 2023). Versatile Synthesis Methods Al2O3 NPs can be synthesized using various methods, including sol-gel synthesis, precipitation, and thermal decomposition of precursor compounds. These synthesis techniques offer control over the particle size, shape, and surface properties, enabling tailored nanoparticles for specific requirements (Said et al., 2020a, b). Sol-­ gel synthesis is a commonly used method to produce aluminum NPs. It involves the hydrolysis and condensation of aluminum precursors to form a sol, which undergoes gelation and subsequent drying to obtain nanoparticles. This technique provides control over particle size, shape, and surface properties by adjusting precursor concentration, pH, and drying conditions (Bokov et al., 2021). The precipitation method involves the chemical reaction between aluminum salts and precipitating agents. This method allows control over particle size and morphology by manipulating reaction parameters, such as temperature, reactant concentrations, and stirring rate. It offers versatility in tailoring nanoparticles for specific applications (Kong et al., 2012). Thermal decomposition involves the decomposition at high temperatures of precursor compounds, such as aluminum salts, to produce Al2O3 NPs. This method provides control over the particle size by adjusting the decomposition temperature and duration. It is commonly used for the synthesis of high-purity Al-NPs for applications such as transparent alumina ceramics (Park et al., 2005). Biocompatibility. These nanoparticles have shown biocompatibility in certain biomedical applications. They have been investigated for drug delivery systems, biosensors, and tissue engineering. They offer the potential to be used as carriers for controlled release of therapeutic agents (La Flamme et al., 2007). The nanoparticles can also be functionalized to enhance their stability, biocompatibility, and drug-loading capacity (Hassanpour et al., 2018). Al2O3 NPs have shown promise in biosensing applications. They can be utilized as sensing elements or immobilization matrices in biosensors. Their biocompatibility enables interactions with biomolecules, facilitating the detection and quantification of various analytes with high sensitivity and specificity (Malik et al., 2021).

272

R. C. Congreve et al.

Al-NPs have been explored in tissue engineering applications. They can be incorporated into scaffolds or coatings to promote cell adhesion, proliferation, and differentiation. The biocompatibility of these nanoparticles allows for their integration into biological systems for regenerative medicine purposes (Bianchi et al., 2022). Disadvantages of Al2O3 NPs Toxicity Concerns Although aluminum NPs are generally considered safe, their potential toxicity is still a subject of ongoing research. It is important to exercise caution and follow proper safety guidelines when handling these nanoparticles (Sliwinska et al., 2015). Some of them are: • Use appropriate personal protective equipment, such as lab coats, gloves, safety goggles, and respiratory protection, to prevent direct skin contact, inhalation, or accidental ingestion of nanoparticles. • Implement engineering controls, such as fume hoods or glove boxes, to contain and control the release of nanoparticles during handling and experimentation. • Ensure good ventilation in the working area to reduce airborne nanoparticle concentrations. • Minimize processes that can generate aerosols or fine particles, as these can be easily inhaled or dispersed in the environment. • Store aluminum nanoparticles in appropriate containers and label them clearly to avoid cross-contamination and accidental exposure. • Follow proper waste disposal guidelines for nanomaterials, ensuring that they are disposed of safely and in compliance with local regulations. Studies investigate the effects of these nanoparticles on cellular systems, including their ability to induce oxidative stress, inflammation, and other adverse responses. These investigations contribute to the overall understanding of their safety profile (Samrot et al., 2023). The potential toxicity of Al2O3 NPs, along with other nanomaterials, is a subject of risk assessment and regulation. Regulatory bodies and research organizations are actively involved in developing guidelines and frameworks to assess the safety of nanomaterials and ensure their responsible use (Allan et al., 2021). Cost: The synthesis of Al-NPs can be expensive, especially when considering the control of particle size and shape. This factor may limit their widespread use in some applications. Certain synthesis methods may involve complex procedures, specialized equipment, and the use of costly precursor materials, which can contribute to increased production costs. In industries where cost-effectiveness is a crucial factor, alternative materials or synthesis methods may be preferred (Khan et al., 2019). Agglomeration: Nanoparticles tend to agglomerate, forming larger clusters or aggregates. This agglomeration can reduce the effectiveness of their properties or hinder their dispersion in certain applications. This agglomeration can occur due to various factors such as van der Waals forces, electrostatic interactions, and

Aluminum Oxide Nanoparticles: Properties and Applications Overview

273

Brownian motion (Yeap, 2018). Agglomeration may alter their surface area, porosity, and reactivity. Agglomerated nanoparticles may also exhibit different optical, electrical, or mechanical behavior compared to individual dispersed nanoparticles (Zare et al., 2017). Various strategies have been developed to address the agglomeration of nanoparticles. Surface functionalization, through the attachment of stabilizing agents or coatings, can help prevent or reduce agglomeration, promoting better dispersion and maintaining the desired properties of nanoparticles in applications (Ahmad et al., 2022). Surface Reactivity: The high reactivity of the nanoparticle surface can lead to challenges in handling and stability. Interactions with the surrounding environment, in terms of chemical reactions or adsorption, must be studied and controlled. Surface modifications or coatings may be required to address these issues in particular cases (Phan & Haes, 2019). Functional groups or molecules (Silanes, Carboxylic acids, Amines, Polyethylene glycol, Phosphonic acids, Thiol groups, Polymers, and Biomolecules) can be attached to the nanoparticle surface, providing control over surface properties, stability, and interaction with the surrounding environment (Sanità et al., 2020).

Emerging Nanomaterial as Antibacterial and Antiviral Agents Some studies have shown that Al-based NPs can exhibit antibacterial effects against a wide range of bacteria (Gudkov et  al., 2022). The small size of nanoparticles allows them to interact with bacterial cell walls and membranes, leading to cell damage and eventual death of the bacteria. This property has potential applications in developing antimicrobial coatings for medical devices, surfaces in hospitals, or even in topical ointments for wound healing. Mechanism of Action  The antibacterial activity of these nanoparticles are attributed to their small size and high surface area-to-volume ratio. Due to their nanoscale dimensions, these particles can interact more effectively with bacterial cell walls and membranes compared to larger particles. The nanoparticles can penetrate the bacterial cell, leading into disruption of the cell wall and membrane integrity (Fig. 3). This can cause leakage of intracellular components and ions, eventually leading to cell death (Mukherjee et al., 2011). More details about how these nanoparticles exert their antibacterial effects are described below: • Small size and high surface area-to-volume ratio: Al2O3 NPs typically have a diameter ranging from a few nanometers to a few hundred nanometers. Because of their small size, a significant portion of the nanoparticles’ atoms lies at the surface, leading to a high surface area-to-volume ratio. This increased surface area provides more sites for interactions with bacterial cells, enhancing their potential antimicrobial activity (Gholizadeh et al., 2023).

274

R. C. Congreve et al.

Fig. 3  Schematic representation of the main mechanisms of the antibacterial action of Al2O3 NPs

• Interaction with bacterial cell walls and membranes: When the nanoparticle comes into contact with bacterial cells, they can readily interact with the cell wall and membrane due to their small size and surface properties. The nanoparticles may attach to the bacterial cell surface through various forces, including van der Waals forces, electrostatic interactions, and hydrogen bonding (Wang et al., 2017). • Disruption of cell wall and membrane integrity: Once inside the bacterial cell, Al-NPs can cause damage to the cell wall and membrane. The nanoparticles may induce structural changes in the cell wall, leading to its destabilization and weakening. As a result, the bacterial membrane’s integrity is compromised (Chen & Bothun, 2014). • Cell death: The leakage of intracellular components and ions disrupts the normal cellular processes, leading to cell death. The loss of essential molecules and ions disrupts the bacterial metabolism and homeostasis, eventually causing the cell to lose its ability to survive and function. As with any antimicrobial agent, careful research and evaluation are necessary to assess the safety, efficacy, and potential environmental impact of Al-NPs. Further studies, including in vivo experiments and clinical trials, are essential to fully understand the scope and limitations of these nanoparticles as broad-spectrum antibacterial agents. Potential Applications Antimicrobial Coatings: Al2O3 NPs can be incorporated into coatings for medical devices, such as catheters, implants, and surgical instruments. These coatings

Aluminum Oxide Nanoparticles: Properties and Applications Overview

275

can help prevent bacterial adhesion and biofilm formation, reducing the risk of infections associated with the use of these devices (Sahoo et al., 2022). Hospital Surfaces: Hospital-acquired infections are a significant concern, and contaminated surfaces in healthcare settings can contribute to their spread. Applying antimicrobial coatings containing Al-NPs to high-touch surfaces, such as doorknobs, bedrails, and countertops, could help reduce the transmission of pathogens and improve hygiene in healthcare facilities (Muller et al., 2016). Wound Healing: Al-NPs can be formulated into topical ointments or dressings to aid in wound healing. By preventing bacterial colonization and infection, these nanoparticles may promote faster and more effective wound closure (Naskar & Kim, 2020). Research on the antiviral properties of these nanoparticles are not as extensive as for antibacterial properties. However, some studies have indicated that these nanoparticles may have inhibitory effects on certain viruses (Sharmin et al., 2021). One potential mechanism proposed for the antiviral activity of nanoparticles, including aluminum NPs, is their ability to disrupt the lipid envelopes of certain viruses. The lipid envelope is a critical component of many viruses, and destabilizing it could render the virus noninfectious (Li et al., 2020). It is important to note that the antiviral activity of nanoparticles can be highly specific to certain viruses and may not extend to all types of viruses. Different viruses have different structures and replication mechanisms, and their interactions with nanoparticles could vary widely.

 oxicity Effect of Al2O3 on Living Cells (A Mechanism T on Living Cells) The evaluation of the cytotoxicity effects of Al2O3 NPs are recent, and results emphasize that the effects depend on the dose, time of exposure, agglomeration, sedimentation, and cellular uptake (Egbuna et  al., 2021). Some studies demonstrated that Al2O3 NPs are nontoxic to L929 murine fibroblasts and normal BJ human skin fibroblasts cells. Rajiv et al. evaluated the cytotoxicity and genotoxicity of different metal oxide nanoparticles (cobalt, iron, silicon, and aluminum) toward human lymphocyte cell lines (Rajiv et al., 2016). The result revealed that alumina nanoparticles exhibited the least oxidative stress–mediated DNA damage, compared to other metal oxide nanoparticles. On the other hand, it has been demonstrated that they can induce genotoxicity toward BEAS-2B mammalian cell lines and brain neuroblastoma cell lines via reactive oxygen species (ROS) production and oxidative stress. Kermani et al. explored the biological responses of the nervous system to Al2O3 NPs using tau protein and neuroblastoma cell line (SH-SY5Y) as targets in vitro (Kermani et al., 2018). The results demonstrated that Al2O3 NPs bind to tau protein forming a static complex that alter the structure of tau, producing a more packed structure. The NPs bind to the hydrophilic residues of the tau segments, promoting

276

R. C. Congreve et al.

structural folding. Cellular assays showed that Al2O3 NPs can elicit cell death through membrane leakage, capsase-9/-3 activations, and induction of both apoptosis and necrosis. The potential toxic effects of alumina NPs on the aquatic environment are also important due to their use in many areas and their unplanned release into the environment (Mukherjee & Acharya, 2018). The main effect of metal oxide nanoparticles, like Al2O3, is generating ROS and exertion of oxidative stress. Nevertheless, Al2O3 is much less toxic when compared to ZnO, CuO, or TiO2 NPs. ROS interact with different biomolecules, including proteins, lipids, and DNA, breaking DNA strands, or altering their expression. It also alters the biological system’s ability to detoxify the reactive intermediates or to repair cellular damage. ROS produce oxidative damage to the cell membrane, impairing the whole functioning of the cell. Nile fish, Oreochromis niloticus, is a good biological model with widespread use in ecotoxicology research. Alumina NPs significantly reduced the antioxidant activity of enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in Oreochromis niloticus (Temiz & Kargın, 2022), causing oxidative damage. Changes in oxidative stress parameters, stress protein, and genotoxicity parameters were the main impact of alumina NPs in this fish. The genotoxic effect of orally administered Al2O3 NPs has also been validated in an in vivo study in rats’ bone marrow cells by chromosomal aberration method. Another consideration in terms of toxicity with metal oxide NPs are in regard to their solubility in aqueous phase (Mukherjee & Acharya, 2018). The released metal ion can exert toxicity by: (1) inducing ROS generation inside the cell, (2) chelating biomolecules, (3) inactivating metalloproteins, and (4) disrupting the cellular metal cation homeostasis.

Antiviral (COVID-19) and Antimicrobial Characteristics Aluminum nanoparticles can be used in the development of vaccines for Middle East respiratory syndrome (MERS-CoV) and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Han et  al., 2021a, b). There are different vaccine platforms developed for these viruses: inactivated viruses, viral vectors (replicating and nonreplicating), mRNA vaccines, DNA vaccines, and protein subunit vaccines. Most of the vaccines developed until now for SARS-CoV-2 have focused on the S protein as the main antigen (Mao et al., 2021). For an effective immune response, a vaccine needs an antigen, a delivery system, and/or an adjuvant (immune enhancer). Many of the vaccine platforms for SARS-­ CoV-­2, based on the inactivated virus or protein subunits, are poorly immunogenic and need an adjuvant to boost the immune response. Adjuvants accelerate, expand, and amplify immunity responses, reducing the antigen dosage in the vaccine and the frequency of immunization (Zhang et al., 2023). However, there are a limited number of adjuvants that are licensed for human vaccines.

Aluminum Oxide Nanoparticles: Properties and Applications Overview

277

The first human adjuvant approved by the Food and Drug Administration (FDA) was aluminum, which is still used as a safe adjuvant against viral infections (Mao et al., 2021). There are two aluminum adjuvants mainly used: aluminum hydroxide and aluminum phosphate (Li et al., 2014; Lu & Liu, 2022). In both cases, it has been shown that the adjuvant activity depends on the size of the particulates that these adjuvants can form. Usually, in an aqueous solution, both aluminum hydroxide and aluminum phosphate form microparticles of around 1–20  μm (Mallamace et  al., 2022). It has been demonstrated that aluminum hydroxide nanoparticles of 200 nm or less have a more potent adjuvant activity than large microparticles. Smaller nanoparticles can absorb much more antigens, facilitate the uptake of antigens by antigen-presenting cells (APC), and induce the expression of histocompatibility complexes and other costimulatory molecules (Lu & Liu, 2022). The response induced by NPs are also more robust and durable. Aluminum hydroxide nanoparticles have been added as adjuvants in vaccines for SARS-CoV-2 like Sinovac (Han et al., 2021a, b). Preclinical studies have demonstrated that aluminum nanoparticles can also be applied in cancer immunotherapies (Mallamace et al., 2022). The differences in adjuvant activity between aluminum microparticles (Al-MPs) and aluminum nanoparticles (Al-NPs) are due to the type of immune response they preferably induce (Mallamace et al., 2022). Notwithstanding Al-MPs bias toward type 2 (Th2) humoral immunity, Al-NPs have a more balanced Th1 and Th2 responses. Type 1 immunity, which depends on cytokines that induce a strong cellular response, is important against intracellular pathogens and also preferred for immunotherapies (Fig. 4). Other interesting materials are zeolite nanoparticles with an aluminosilicate composition (Derakhshankhah et  al., 2020). Their three-dimensional structure encompasses pores and cavities that make them a good support material, or host matrix, to encapsulate and stabilize metal oxide nanoparticles like Cu2O (Jampa

Fig. 4  Immune responses induced by Al-NPs adjuvants

278

R. C. Congreve et al.

et  al., 2022). Cu2O nanoparticles have shown a broad spectrum of antibacterial activity, including SARS-CoV-2. Cu2O in zeolite (CuZ) can be used as a coating films on plastic substrates, demonstrating a reduction of 99.93% of porcine coronavirus (porcine epidemic diarrhea virus, PEDV) and 99.94% of SARS-CoV-2 viruses, in 5 min of contact time. Also, the CuZ film is more transparent than other commercial products and less toxic and skin irritating than pristine Cu2O nanoparticles on their own.

Recent Studies on Antimicrobial and Antiviral Applications Al-NPs are cost-effective nanomaterials with high surface area, mechanical strength, thermostability, and resistance to harsh conditions (Hassanpour et al., 2018). They also have a surface that can be easily functionalized, which makes them particularly interesting for their use in biomedicine and biotechnology. Some examples of their applications in biomedicine, which include antimicrobial effects, immunotherapy, biosensing, biomolecule stabilization, drug delivery, and diverse therapies, are summarized in Table 1. Al2O3 NPs have a high antimicrobial activity (Kermani et  al., 2018). There is evidence of its inherent ability against gram-positive and gram-negative bacteria in vitro (Manyasree et al., 2018; Sharma & Sharma, 2020). Also, fibrous type alumina nanoparticles, covalently bound to antimicrobial peptides, have shown antimicrobial activity against both bacteria and fungi (Torres et al., 2019). Given their high biocompatibility, this material is a promising nanobiomaterial to avoid infection and rejection of medical devices, like orthodontic or orthopedic implants. When coated with aluminum, ZnO nanoparticles have shown an enhanced antibacterial activity on pathogens like Escherichia coli, Proteus mirabilis, Enterococcus faecalis, and Staphylococcus aureus (Chidhambaram, 2019). The highest antibacterial efficiency was obtained with 5% Al:ZnO nanoparticles. In another study, functionalization of the surface of Fe3O4 NPs with an alumina coating (alumina-coated iron oxide magnetic nanoparticles) converted them into photothermal agents to selectively kill bacteria (Yu et al., 2011).

Future Use As a future use, Al-NPs are seen in different fields of application, some of them are as follows: Antimicrobial Applications: Al2O3, boasts exceptional properties that could make it a revolutionary material for future antibacterial and antiviral applications. Scientists have discovered that it could be used to create antimicrobial surfaces, such as coatings for medical devices and equipment, as well as air filtration systems. Its ability to prevent the growth of

Aluminum Oxide Nanoparticles: Properties and Applications Overview

279

Table 1  Biomedical applications of alumina NPs Application Antimicrobial effects

Immunotherapy

Biosensing

Biomolecular stabilization Drug delivery

Therapy

Examples Strong antimicrobial activities Antifungi Photothermal killing effects Leishmania vaccine to induce autophagy in macrophages Potent vaccination adjuvant Bovine serum albumin DNA detection Hydroquinone Nanoplatform for correct refolding of mis−/unfolded proteins Oral delivery of anti-blood pressure drug Telmisartan

Ibuprofen (sol-gel of aluminum oxide-ibuprofen nanocomposite) Anticancer therapy Cytotoxic agents for human prostate cancer cells Changing the zeta potential of cell surface for cancer Boosting the efficacy of cancer vaccines Anti-asthmatic Nano-thrombolytic system

Reference Chidhambaram (2019), Manyasree et al. (2018) and Sharma & Sharma (2020) Torres et al. (2019) Yu et al. (2011) Beyzay et al. (2017) Mallamace et al. (2022) Ito et al. (2017) Aramesh et al. (2017) Liu et al. (2011) Volodina et al. (2017)

“Design and fabrication of ordered mesoporous alumina scaffold for drug delivery of poorly water soluble drug” (2023) Tarlani et al. (2017)

F. Wang et al. (2016) Rajan et al. (2015) Sergey et al. (2016) Li et al. (2011) Athari et al. (2016) Chapurina et al. (2016)

bacteria and viruses makes it a highly promising contender for use in various healthcare and public health settings. Additionally, Al2O3 nanoparticles have exhibited potential in drug delivery systems designed to combat bacterial and viral infections. These applications underscore the immense potential of Al2O3 in the fight against infectious diseases. Energy Storage and Conversion: This kind of nanoparticles offers potential benefits in advanced energy storage devices, including lithium-ion batteries and supercapacitors, by improving their performance and efficiency (Islam et  al., 2023). These nanoparticles can be employed as electrode materials, offering several advantages: 1. Improved Charge Storage Capacity: The high surface area enables more active sites for electrochemical reactions, facilitating increased charge storage capacity in energy storage devices. This results in higher energy density and improved overall performance.

280

R. C. Congreve et al.

2. Faster Charging/Discharging Rates: The small size of Al-NPs allows for shorter diffusion pathways for ions within the electrode material. As a result, the nanoparticles facilitate faster ion transport during the charging and discharging processes, leading to reduced charging time and enhanced power output. 3. Enhanced Cyclic Stability: They exhibit excellent stability and resistance to degradation over repeated charge and discharge cycles. They can withstand the stresses and strains associated with repetitive electrochemical reactions, thus contributing to enhanced cyclic stability and prolonged lifespan of energy storage devices. By incorporating Al-NPs into the electrode materials of lithium-ion batteries and supercapacitors, these devices can benefit from increased charge storage capacity, faster charging/discharging rates, and improved cyclic stability. Such improvements are crucial for meeting the growing demand for high-performance energy storage systems in applications ranging from portable electronics to electric vehicles and renewable energy integration (Lakshmi & Vedhanarayanan, 2023). Water Treatment and Purification: Aluminum NPs have the potential to play a significant role in water treatment technologies due to their ability to remove various contaminants, including heavy metals, organic pollutants, and microorganisms (Naseem & Durrani, 2021). The following details shed light on their application as effective adsorbents or catalysts for water purification processes: 1. High Surface Area: They possess a high surface area, thanks to their nanoscale size and large surface area-to-volume ratio. This high surface area provides more active sites for interactions with contaminants, allowing for greater adsorption and catalytic potential. 2. Adsorption Properties: Their strong adsorption properties make them effective adsorbents for water treatment. They can adsorb a wide range of contaminants, including heavy metal ions (such as lead, arsenic, and cadmium) and organic pollutants (such as dyes, pesticides, and pharmaceuticals). The nanoparticles’ surface properties can be tailored through surface modifications or functionalization to enhance their adsorption capacity for specific contaminants. 3. Catalytic Properties: In addition to their adsorption capabilities, these nanoparticles can also act as catalysts in water purification processes. They can facilitate various catalytic reactions, such as oxidation or reduction reactions, to degrade or transform contaminants into less harmful forms. For example, they can catalyze the degradation of organic pollutants through advanced oxidation processes (AOPs) such as photocatalysis or Fenton-like reactions. 4. Microorganism Inactivation: Al-NPs nanoparticles also exhibit antimicrobial properties, enabling them to effectively inhibit the growth and activity of microorganisms in water. They can act as disinfectants by damaging the cell walls or interfering with cellular functions of bacteria, viruses, and other microorganisms, thus aiding in water disinfection and microbial control.

Aluminum Oxide Nanoparticles: Properties and Applications Overview

281

The high surface area, strong adsorption properties, and catalytic potential of Al-NPs make them promising candidates for various water treatment applications, including the removal of heavy metals, organic pollutants, and microorganisms. Continued research and development in this area hold the potential to advance water purification technologies and address global water quality challenges (Ahmad et al., 2022). Optoelectronic Devices: Al-NPs possess unique optical properties that make them promising for use in optoelectronic devices, including light-emitting diodes (LEDs) and solar cells. The following details provide more information on their applications and benefits: 1. Phosphor Materials in LEDs: They can be utilized as phosphor materials in LEDs to enhance their light emission efficiency and color rendering capabilities. When excited by an external energy source, these nanoparticles can emit light of specific wavelengths, contributing to improved brightness and color accuracy in LEDs. By controlling the composition and size of the nanoparticles, the emitted light can be fine-tuned to achieve desired color outputs. 2. Light Scattering Layers in Solar Cells: Solar cells can be employed as light scattering layers. These nanoparticles possess a high refractive index, enabling efficient scattering of incoming light. By scattering the incident light multiple times within the solar cell, the effective optical path length of the light is increased, enhancing light absorption by the active material. This leads to improved light harvesting and increased energy conversion efficiency in solar cells. 3. Antireflection Coatings in Solar Cells: They can also be applied as antireflection coatings in solar cells. The nanoparticles can be deposited on the surface of the solar cell to minimize reflection losses by reducing the refractive index mismatch between the air and the cell. This allows a higher percentage of incident light to enter the solar cell, thereby enhancing light absorption and overall energy conversion efficiency. By incorporating Al-NPs in optoelectronic devices, such as LEDs and solar cells, their unique optical properties can be harnessed to improve device performance, including enhanced light emission efficiency, color rendering, light absorption, and energy conversion efficiency (Leung et al., 2014). Antireflective Coatings: The incorporation of aluminum NPs into coatings offers the potential to reduce reflection and improve light transmission properties (Smith et al., 2018). Here are further details on their applications and benefits: 1. Reduction of Reflection: These nanoparticles can be integrated into coatings to minimize unwanted reflection of light. Due to their high refractive index and unique optical properties, these nanoparticles can effectively reduce the amount of light that is reflected at the interface between different materials. By reducing reflection, coatings with aluminum oxide nanoparticles enhance light transmission through the coated surface.

282

R. C. Congreve et al.

2. Enhanced Light Transmission: The incorporation of Al-NPs into coatings can lead to improved light transmission properties. The nanoparticles can scatter light, effectively redirecting it and allowing it to propagate through the coating with reduced losses. This scattering effect enables a more uniform distribution of light and increased transmission through the coated surface, leading to enhanced brightness and clarity. 3. Wide Range of Applications: Coatings with these nanoparticles find applications in various fields where reflection reduction and improved light transmission are crucial. For example: Solar Panels: Al-NPs coatings can be applied to solar panels to minimize reflection losses and enhance the capture of sunlight, thereby improving the overall energy conversion efficiency. Optical Lenses: Coatings incorporating aluminum NPs on optical lenses help to reduce glare and enhance light transmission, resulting in improved visual clarity and image quality. Display Technologies: The use of Al-NPs coatings on display screens, such as LCDs and OLEDs, reduces reflection and enhances contrast, leading to better viewing experiences and reduced eyestrain. By incorporating these nanoparticles into coatings, various industries can benefit from reduced reflection, enhanced light transmission, and improved overall performance in applications where the control of light propagation is crucial (Smith et al., 2018).

Conclusion In conclusion, Al2O3 nanoparticles possess unique properties that make them attractive for various applications. Some of these properties are their high surface area, high hardness, thermal stability, biocompatibility, surface functionalization, and electrical insulation. They are also chemically inert and resistant to corrosion. These nanoparticles find applications in catalysis, electronics, optics, energy storage, biomedical field, and abrasive applications. Regarding their potential toxicity, Al-NPs’ safety and impact on living cells are still under investigation. While they are generally considered biocompatible, their potential toxicity depends on factors, such as concentration, exposure duration, agglomeration, sedimentation, and cellular uptake. Of all metal oxide nanoparticles, Al-NPs exhibited the least oxidative stress–mediated DNA damage. Still, they can induce ROS oxidative damage in cells and have shown genotoxic effects in some biological models. Looking ahead, Al-NPs are promising elements in advanced materials and coatings, energy storage systems, catalysis, biomedical applications, environmental remediation, optoelectronics and photonics, and personal care products. However, further research and development are necessary to optimize their properties, performance, and safety in these specific areas.

Aluminum Oxide Nanoparticles: Properties and Applications Overview

283

References Ahmad, F., Salem-Bekhit, M.  M., Khan, F., Alshehri, S., Khan, A., Ghoneim, M.  M., et  al. (2022). Unique properties of surface-functionalized nanoparticles for bio-application: Functionalization mechanisms and importance in application. Nanomaterials, 12(8). https:// doi.org/10.3390/nano12081333 Allan, J., Belz, S., Hoeveler, A., Hugas, M., Okuda, H., Patri, A., et al. (2021). Regulatory landscape of nanotechnology and nanoplastics from a global perspective. Regulatory Toxicology and Pharmacology, 122, 104885. https://doi.org/10.1016/J.YRTPH.2021.104885 Altammar, K.  A. (2023). A review on nanoparticles: Characteristics, synthesis, applications, and challenges. Frontiers in Microbiology, 14(April), 1–20. https://doi.org/10.3389/ fmicb.2023.1155622 Aramesh, M., Tran, P. A., Ostrikov, K., & (Ken), & Prawer, S. (2017). Conformal nanocarbon coating of alumina nanocrystals for biosensing and bioimaging. Carbon, 122, 422–427. https://doi. org/10.1016/J.CARBON.2017.06.101 Athari, S.  S., Pourpak, Z., Folkerts, G., Garssen, J., Moin, M., Adcock, I.  M., et  al. (2016). Conjugated alpha-alumina nanoparticle with vasoactive intestinal peptide as a Nano-drug in treatment of allergic asthma in mice. European Journal of Pharmacology, 791, 811–820. https://doi.org/10.1016/J.EJPHAR.2016.10.014 Baek, Y., Lim, S., Ho, L., Park, S., Woo, S., Hwan, T., et al. (2016). Al2 O3/TiO2 nanolaminate gate dielectric fi lms with enhanced electrical performances for organic fi eld-effect transistors. Organic Electronics, 28, 139–146. https://doi.org/10.1016/j.orgel.2015.10.025 Balasubramanyam, A., Sailaja, N., Mahboob, M., Rahman, M.  F., Hussain, S.  M., & Grover, P. (2010). Toxicology in vitro in vitro mutagenicity assessment of aluminium oxide nanomaterials using the Salmonella/microsome assay. Toxicology In Vitro, 24(6), 1871–1876. https:// doi.org/10.1016/j.tiv.2010.07.004 Beaton, G., Zacks, J., & Stamplecoskie, K. (2022). Al2O3 anchored silver and gold nanoparticles as accessible, stable, and re-usable catalysts. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 646, 128972. https://doi.org/10.1016/J.COLSURFA.2022.128972 Beyzay, F., Hosseini, A. Z., & Soudi, S. (2017). Alpha alumina nanoparticle conjugation to cysteine peptidase a and B: An efficient method for autophagy induction. Avicenna Journal of Medical Biotechnology, 9(2), 71. Retrieved from /pmc/articles/PMC5410132/. Bianchi, E., Vigani, B., Viseras, C., Ferrari, F., Rossi, S., & Sandri, G. (2022). Inorganic nanomaterials in tissue engineering. Pharmaceutics, 14(6). https://doi.org/10.3390/pharmaceutics14061127 Bokov, D., Jalil, A. T., Chupradit, S., Suksatan, W., Ansari, M. J., Shewael, I. H., et al. (2021). Nanomaterial by sol-gel method: synthesis and application. Adv Mater Sci Eng, 2021, 5102014. Chapurina, Y.  E., Drozdov, A.  S., Popov, I., Vinogradov, V.  V., Dudanov, I.  P., & Vinogradov, V.  V. (2016). Streptokinase@alumina nanoparticles as a promising thrombolytic colloid with prolonged action. Journal of Materials Chemistry B, 4(35), 5921–5928. https://doi. org/10.1039/C6TB01349J Chavali, M.  S., Nikolova, M.  P., & Silver, A. (2019). Metal oxide nanoparticles and their applications in nanotechnology. SN Applied Sciences, 1(6), 1–30. https://doi.org/10.1007/ s42452-­019-­0592-­3 Chen, K. L., & Bothun, G. D. (2014). Nanoparticles meet cell membranes: Probing nonspecific interactions using model membranes. Environmental Science and Technology, 48(2), 873–880. https://doi.org/10.1021/es403864v Chidhambaram, N. (2019). Augmented antibacterial efficacies of the aluminium doped ZnO nanoparticles against four pathogenic bacteria. Materials Research Express, 6(7). https://doi. org/10.1088/2053-­1591/AB1804 Daroughegi, R., Meshkani, F., & Rezaei, M. (2019). Characterization and evaluation of mesoporous high surface area promoted Ni- Al2O3 catalysts in CO2 methanation. Journal of the Energy Institute. https://doi.org/10.1016/j.joei.2019.07.003

284

R. C. Congreve et al.

Derakhshankhah, H., Jafari, S., Sarvari, S., Barzegari, E., Moakedi, F., Ghorbani, M., et al. (2020). Biomedical applications of Zeolitic nanoparticles, with an emphasis on medical interventions (Vol. 15, p. 363). https://doi.org/10.2147/IJN.S234573 Design and Fabrication of Ordered Mesoporous Alumina Scaffold for Drug Delivery of Poorly Water Soluble Drug. (2023). https://austinpublishinggroup.com/therapeutics/fulltext/ therapeutics-­v2-­id1015.php Egbuna, C., Parmar, V. K., Jeevanandam, J., Ezzat, S. M., Patrick-Iwuanyanwu, K. C., Adetunji, C.  O., et  al. (2021). Toxicity of nanoparticles in biomedical application: Nanotoxicology. Journal of Toxicology, 2021, 1. https://doi.org/10.1155/2021/9954443 Fawcett, D. (2011). Significance of novel bioinorganic anodic aluminum oxide nanoscaffolds for promoting cellular response (Vol. 4, p. 11). https://doi.org/10.2147/NSA.S13913 Förster, G. D. (2020). Influence of oxidizing conditions on the condensation of aluminum oxide nanoparticles: Insights from atomistic modeling. Applied Surface Science, 512, 145440. Gholizadeh, Z., Aliannezhadi, M., Ghominejad, M., & Tehrani, F. S. (2023). High specific surface area γ-Al2O3 nanoparticles synthesized by facile and low-cost co-precipitation method. Scientific Reports, 13(1), 1–14. https://doi.org/10.1038/s41598-­023-­33266-­0 Girimurugan, K., Arunraja, M., Shanmugam, A., & Saranya, S.  M. V. (2023). The effects of nano-alumina particles on the enrichment of tensile, flexural and impact properties of carbon fiber-reinforced epoxy composites. Materials Today: Proceedings. https://doi.org/10.1016/j. matpr.2023.04.053 Gudkov, S. V., Burmistrov, D. E., Smirnova, V. V., Semenova, A. A., & Lisitsyn, A. B. (2022). A mini review of antibacterial properties of Al2O3 nanoparticles. Nanomaterials, 12(15), 1–17. https://doi.org/10.3390/nano12152635 Guerrero-Arguero, I., Khan, S. R., Henry, B. M., Garcia-Vilanova, A., Chiem, K., Ye, C., et al. (2023). Mitigation of SARS-CoV-2 by using transition metal Nanozeolites and quaternary ammonium compounds as antiviral agents in suspensions and soft fabric materials. International Journal of Nanomedicine, 18(May), 2307–2324. https://doi.org/10.2147/IJN.S396669 Hameed, A. Z., & Muralidharan, K. (2023). Performance, emission, and catalytic activity analysis of AL2O3 and CEO2 Nano-additives on diesel engines using Mahua biofuel for a sustainable environment. ACS Omega, 8(6), 5692–5701. https://doi.org/10.1021/acsomega.2c07193 Han, B., Song, Y., Li, C., Yang, W., Ma, Q., Jiang, Z., et al. (2021a). Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: A double-blind, randomised, controlled, phase 1/2 clinical trial. The Lancet Infectious Diseases, 21(12), 1645–1653. https://doi.org/10.1016/S1473-­3099(21)00319-­4 Han, H.  J., Nwagwu, C., Anyim, O., Ekweremadu, C., & Kim, S. (2021b). COVID-19 and cancer: From basic mechanisms to vaccine development using nanotechnology. International Immunopharmacology, 90(November 2020), 107247. https://doi.org/10.1016/j. intimp.2020.107247 Harish, V., Tewari, D., Gaur, M., Yadav, A. B., & Swaroop, S. (2022). Review on nanoparticles and nanostructured materials: Bioimaging, biosensing, drug delivery, tissue engineering, antimicrobial, and agro-food applications. Nanomaterials, 12. Hassanpour, P., Panahi, Y., Ebrahimi-kalan, A., Akbarzadeh, A., Davaran, S., Nasibova, A. N., et al. (2018). Biomedical applications of aluminium oxide nanoparticles, 13, 1227–1231. https://doi. org/10.1049/mnl.2018.5070 Islam, M. S., Mubarak, M., & Lee, H. J. (2023). Hybrid nanostructured materials as electrodes in energy storage devices. Inorganics, 11(5), 1–21. https://doi.org/10.3390/inorganics11050183 Ito, T., Matsuda, Y., Jinba, T., Asai, N., Shimizu, T., & Shingubara, S. (2017). Fabrication and characterization of nano porous lattice biosensor using anodic aluminum oxide substrate. Japanese Journal of Applied Physics, 56(6), 06GG02. https://doi.org/10.7567/JJAP.56.06GG02/XML Jampa, S., Ratanatawanate, C., Pimtong, W., Aueviriyavit, S., Chantho, V., Sillapaprayoon, S., et al. (2022). Transparent anti-SARS COV-2 film from copper(I) oxide incorporated in zeolite nanoparticles. ACS Applied Materials and Interfaces, 14(46), 52334–52346. https://doi. org/10.1021/acsami.2c12274

Aluminum Oxide Nanoparticles: Properties and Applications Overview

285

Kazantsev, S. O., Fomenko, A. N., & Korovin, M. S. (2016). Zeta potential change of neuro-2a tumor cells after exposure to alumina nanoparticles. AIP Conference Proceedings, 1760(1). https://doi.org/10.1063/1.4960244/782991 Kazantsev, S. O., Lozhkomoev, A. S., Glazkova, E. A., Gotman, I., Gutmanas, E. Y., Lerner, M. I., & Psakhie, S. G. (2018). SC. Materials Research Bulletin, 104, 97. https://doi.org/10.1016/j. materresbull.2018.04.011 Kermani, Z. R., Haghighi, S. S., Hajihosseinali, S., Fashami, A. Z., Akbaritouch, T., Akhtari, K., et al. (2018). Aluminium oxide nanoparticles induce structural changes in tau and cytotoxicity of the neuroblastoma cell line. International Journal of Biological Macromolecules, 120(Pt A), 1140–1148. https://doi.org/10.1016/J.IJBIOMAC.2018.08.182 Khan, I., Saeed, K., & Khan, I. (2019). Nanoparticles: Properties, applications and toxicities. Arabian Journal of Chemistry, 12(7), 908–931. https://doi.org/10.1016/J.ARABJC.2017.05.011 Khan, Y., Sadia, H., Ali Shah, S.  Z., Khan, M.  N., Shah, A.  A., Ullah, N., et  al. (2022). Classification, synthetic, and characterization approaches to nanoparticles, and their applications in various fields of nanotechnology: A review. Catalysts, 12(11). https://doi. org/10.3390/catal12111386 Kong, J., Chao, B., Wang, T., & Yan, Y. (2012). Preparation of ultrafine spherical AlOOH and Al2O3 powders by aqueous precipitation method with mixed surfactants. Powder Technology, 229, 7–16. https://doi.org/10.1016/J.POWTEC.2012.05.024 La Flamme, K.  E., Popat, K.  C., Leoni, L., Markiewicz, E., La Tempa, T.  J., Roman, B.  B., et  al. (2007). Biocompatibility of nanoporous alumina membranes for immunoisolation. Biomaterials, 28(16), 2638–2645. https://doi.org/10.1016/J.BIOMATERIALS.2007.02.010 Lakshmi, K.  C. S., & Vedhanarayanan, B. (2023). High-performance supercapacitors: A comprehensive review on paradigm shift of conventional energy storage devices. Batteries, 9(4). https://doi.org/10.3390/batteries9040202 Lee, J. H., Hwang, K. S., Jang, S. P., Lee, B. H., Kim, J. H., Choi, S. U. S., & Choi, C. J. (2008). Effective viscosities and thermal conductivities of aqueous nanofluids containing low volume concentrations of Al2O3 nanoparticles. International Journal of Heat and Mass Transfer, 51(11–12), 2651–2656. https://doi.org/10.1016/j.ijheatmasstransfer.2007.10.026 Leung, S. F., Zhang, Q., Xiu, F., Yu, D., Ho, J. C., Li, D., & Fan, Z. (2014). Light management with nanostructures for optoelectronic devices. Journal of Physical Chemistry Letters, 5(8), 1479–1495. https://doi.org/10.1021/jz500306f Li, H., Li, Y., Jiao, J., & Hu, H. M. (2011). Alpha-alumina nanoparticles induce efficient autophagy-­ dependent cross-presentation and potent antitumour response. Nature Nanotechnology, 6(10), 645–650. https://doi.org/10.1038/nnano.2011.153 Li, X., Aldayel, A.  M., & Cui, Z. (2014). Aluminum hydroxide nanoparticles show a stronger vaccine adjuvant activity than traditional aluminum hydroxide microparticles. Journal of Controlled Release, 173(1), 148–157. https://doi.org/10.1016/j.jconrel.2013.10.032 Li, Y., Xiao, Y., Chen, Y., & Huang, K. (2020). Nano-based approaches in the development of antiviral agents and vaccines. Life Sciences, 265, 118761. Liu, X., Luo, L., Ding, Y., & Xu, Y. (2011). Amperometric biosensors based on alumina nanoparticles-­chitosan-horseradish peroxidase nanobiocomposites for the determination of phenolic compounds. Analyst, 136(4), 696–701. https://doi.org/10.1039/C0AN00752H Lu, Y., & Liu, G. (2022). Nano alum: A new solution to the new challenge. Human Vaccines and Immunotherapeutics, 18(5). https://doi.org/10.1080/21645515.2022.2060667 Malik, P., Gupta, R., Malik, V., & Ameta, R. K. (2021). Emerging nanomaterials for improved biosensing. Measurement: Sensors, 16, 100050. https://doi.org/10.1016/J.MEASEN.2021.100050 Mallamace, F., Nazarizadeh, A., Staudacher, A. H., Wittwer, N. L., Turnbull, T., Brown, M. P., & Kempson, I. (2022). Aluminium nanoparticles as efficient adjuvants compared to their microparticle counterparts: Current progress and perspectives. International Journal of Molecular Sciences, 23. https://doi.org/10.3390/ijms23094707 Manikandan, V., Jayanthi, P., Priyadharsan, A., Vijayaprathap, E., Anbarasan, P. M., & Velmurugan, P. (2019). Green synthesis of pH-responsive Al2O3 nanoparticles: Application to rapid removal

286

R. C. Congreve et al.

of nitrate ions with enhanced antibacterial activity. Journal of Photochemistry and Photobiology A: Chemistry, 371, 205–215. https://doi.org/10.1016/J.JPHOTOCHEM.2018.11.009 Manyasree, D., Kiranmayi, P., & Ravi Kumar, R. V. S. N. (2018). Sythesis, characterization and antibacterial activity of aluminium oxide nanoparticles. International Journal of Pharmacy and Pharmaceutical Sciences, 10(1), 32. https://doi.org/10.22159/ijpps.2018v10i1.20636 Mao, L., Chen, Z., Wang, Y., & Chen, C. (2021). Design and application of nanoparticles as vaccine adjuvants against human corona virus infection. Journal of Inorganic Biochemistry, 219(March), 111454. https://doi.org/10.1016/j.jinorgbio.2021.111454 Martin, C., Nourian, A., Babaie, M., & Nasr, G.  G. (2023). Geoenergy science and engineering environmental, health and safety assessment of nanoparticle application in drilling mud – Review. Geoenergy Science and Engineering, 226(April), 211767. https://doi.org/10.1016/j. geoen.2023.211767 Mohammed, A. A., Khodair, Z. T., & Khadom, A. A. (2020). Preparation, characterization and application of Al2O3 nanoparticles for the protection of boiler steel tubes from high temperature corrosion. Ceramics International. https://doi.org/10.1016/j.ceramint.2020.07.172 Mukherjee, K., & Acharya, K. (2018). Toxicological effect of metal oxide nanoparticles on soil and aquatic habitats. Archives of Environmental Contamination and Toxicology, 75(2), 175–186. https://doi.org/10.1007/S00244-­018-­0519-­9/FIGURES/4 Mukherjee, A., Tc, P., & Chandrasekaran, N. (2011). Antimicrobial activity of aluminium oxide nanoparticles for potential clinical applications antimicrobial activity of aluminium oxide nanoparticles for potential clinical applications, (May 2014). Science against Microbial Pathogense Communicating Current Research and Technological Advances, 1, 245–251. Muller, M. P., MacDougall, C., Lim, M., Armstrong, I., Bialachowski, A., Callery, S., et al. (2016). Antimicrobial surfaces to prevent healthcare-associated infections: A systematic review. Journal of Hospital Infection, 92(1), 7–13. https://doi.org/10.1016/j.jhin.2015.09.008 Naseem, T., & Durrani, T. (2021). The role of some important metal oxide nanoparticles for wastewater and antibacterial applications: A review. Environmental Chemistry and Ecotoxicology, 3, 59–75. https://doi.org/10.1016/J.ENCECO.2020.12.001 Nasiri, H., Motlagh, E.  B., Khaki, J.  V., & Zebarjad, S.  M. (2012). Role of fuel/oxidizer ratio on the synthesis conditions of Cu  – Al2 O3 nanocomposite prepared through solution combustion synthesis. Materials Research Bulletin, 47(11), 3676–3680. https://doi.org/10.1016/j. materresbull.2012.06.041 Naskar, A., & Kim, K. S. (2020). Recent advances in nanomaterial-based wound-healing therapeutics. Pharmaceutics, 12(6). https://doi.org/10.3390/pharmaceutics12060499 Niroumandrad, S., Rostami, M., & Ramezanzadeh, B. (2016). Effects of combined surface treatments of aluminium nanoparticle on its corrosion resistance before and after inclusion into an epoxy coating. Progress in Organic Coatings, 101, 486–501. https://doi.org/10.1016/j. porgcoat.2016.09.010 Park, Y. K., Tadd, E. H., Zubris, M., & Tannenbaum, R. (2005). Size-controlled synthesis of alumina nanoparticles from aluminum alkoxides. Materials Research Bulletin, 40(9), 1506–1512. https://doi.org/10.1016/J.MATERRESBULL.2005.04.031 Phan, H. T., & Haes, A. J. (2019). What does nanoparticle stability mean? Journal of Physical Chemistry C, 123(27), 16495–16507. https://doi.org/10.1021/acs.jpcc.9b00913 Pirhady Tavandashti, N., Molana Almas, S., & Esmaeilzadeh, E. (2021). Corrosion protection performance of epoxy coating containing alumina/PANI nanoparticles doped with cerium nitrate inhibitor on Al-2024 substrates. Progress in Organic Coatings, 152(3), 106133. https://doi. org/10.1016/j.porgcoat.2021.106133 Piriyawong, V., Thongpool, V., Asanithi, P., & Limsuwan, P. (2012). Preparation and characterization of alumina nanoparticles in deionized water using laser ablation technique. Journal of Nanomaterials. https://doi.org/10.1155/2012/819403 Rajan, Y.  C., Inbaraj, B.  S., & Chen, B.  H. (2015). Synthesis and characterization of poly(γ-­ glutamic acid)-based alumina nanoparticles with their protein adsorption efficiency and

Aluminum Oxide Nanoparticles: Properties and Applications Overview

287

­cytotoxicity towards human prostate cancer cells. RSC Advances, 5(20), 15126–15139. https:// doi.org/10.1039/C4RA10445E Rajiv, S., Jerobin, J., Saranya, V., Nainawat, M., Sharma, A., Makwana, P., et al. (2016). Comparative cytotoxicity and genotoxicity of cobalt (II, III) oxide, iron (III) oxide, silicon dioxide, and aluminum oxide nanoparticles on human lymphocytes in  vitro. Human and Experimental Toxicology, 35(2), 170–183. https://doi.org/10.1177/0960327115579208/FORMAT/EPUB Ramírez, M., González, R. I., Baltazar, S. E., Rojas-Nunez, J., Allende, S., Valdivia, J. A., et al. (2019). Thermal stability of aluminum oxide nanoparticles: Role of oxygen concentration. Inorganic Chemistry Frontiers, 6(7), 1701–1706. https://doi.org/10.1039/c8qi01398e Riquelme, A., Rodrigo, P., Escalera-Rodriguez, M.  D., & Rams, J. (2022). Wear resistance of aluminum matrix composites’ coatings added on AA6082 aluminum alloy by laser cladding. Coatings, 12(1). https://doi.org/10.3390/coatings12010041 Sahoo, J., Sarkhel, S., Mukherjee, N., & Jaiswal, A. (2022). Nanomaterial-based antimicrobial coating for biomedical implants: New age solution for biofilm-associated infections. ACS Omega, 7(50), 45962–45980. https://doi.org/10.1021/acsomega.2c06211 Said, S., Mikhail, S., & Riad, M. (2020a). Materials science for energy technologies recent processes for the production of alumina nano-particles. Materials Science for Energy Technologies, 3, 344–363. https://doi.org/10.1016/j.mset.2020.02.001 Said, S., Mikhail, S., & Riad, M. (2020b). Recent processes for the production of alumina nano-­ particles. Materials Science for Energy Technologies, 3, 344–363. https://doi.org/10.1016/J. MSET.2020.02.001 Samrot, A. V., Prakash, N. R., & L. X. (2023). Nanoparticles induced oxidative damage in reproductive system and role of antioxidants on the induced toxicity. Life, 13(3), 1–17. https://doi. org/10.3390/life13030767 Sanità, G., Carrese, B., & Lamberti, A. (2020). Nanoparticle surface functionalization: How to improve biocompatibility and cellular internalization. Frontiers in Molecular Biosciences, 7(November). https://doi.org/10.3389/fmolb.2020.587012 Shah, M.  A., Pirzada, B.  M., Price, G., Shibiru, A.  L., & Qurashi, A. (2022). Applications of nanotechnology in smart textile industry: A critical review. Journal of Advanced Research, 38, 55–75. https://doi.org/10.1016/j.jare.2022.01.008 Sharma, P., & Sharma, N. (2020). Antimicrobial activity of alumina nanoparticles synthesized by leaf extract of ocimum sanctum. International Journal of Engineering Applied Sciences and Technology, 5, 251–253. Sharmin, S., Rahaman, M. M., Sarkar, C., Atolani, O., Islam, M. T., & Adeyemi, O. S. (2021). Nanoparticles as antimicrobial and antiviral agents: A literature-based perspective study. Heliyon, 7(3), e06456. https://doi.org/10.1016/j.heliyon.2021.e06456 Sliwinska, A., Kwiatkowski, D., Czarny, P., Milczarek, J., Toma, M., Korycinska, A., et al. (2015). Genotoxicity and cytotoxicity of ZnO and Al2O3 nanoparticles. Toxicology Mechanisms and Methods, 25(3), 176–183. https://doi.org/10.3109/15376516.2015.1006509 Smith, S.  R., Rafati, R., Sharifi Haddad, A., Cooper, A., & Hamidi, H. (2018). Application of aluminium oxide nanoparticles to enhance rheological and filtration properties of water based muds at HPHT conditions. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 537, 361–371. https://doi.org/10.1016/J.COLSURFA.2017.10.050 Tarlani, A., Isari, M., Khazraei, A., & Moghadam, M. E. (2017). New sol-gel derived aluminum oxide-ibuprofen nanocomposite as a controlled releasing medication. Nanomedicine Research Journal, 2(1), 28–35. https://doi.org/10.22034/NMRJ.2017.23256 Temiz, Ö., & Kargın, F. (2022). Toxicological impacts on antioxidant responses, stress protein, and genotoxicity parameters of aluminum oxide nanoparticles in the liver of Oreochromis niloticus. Biological Trace Element Research, 200(3), 1339–1346. https://doi.org/10.1007/ S12011-­021-­02723-­0/FIGURES/2 Torres, L. M. F. C., Almeida, M. T., Santos, T. L., Marinho, L. E. S., de Mesquita, J. P., da Silva, L.  M., et  al. (2019). Antimicrobial alumina nanobiostructures of disulfide- and triazole-­ linked peptides: Synthesis, characterization, membrane interactions and biological a­ ctivity.

288

R. C. Congreve et al.

Colloids and Surfaces B: Biointerfaces, 177(January), 94–104. https://doi.org/10.1016/j. colsurfb.2019.01.052 Volodina, K.  V., Avnir, D., & Vinogradov, V.  V. (2017). Alumina nanoparticle-assisted enzyme refolding: A versatile methodology for proteins renaturation. Scientific Reports, 7(1), 1–7. https://doi.org/10.1038/s41598-­017-­01436-­6 Wang, F., Chen, M., Hu, X., Ye, R., Tan, C., & Ji, L. (2016). Ester-modified Cyclometalated iridium (III) complexes as anticancer agents. Nature Publishing Group, 210(November), 21–23. https://doi.org/10.1038/srep38954 Wang, L., Hu, C., & Shao, L. (2017). The-antimicrobial-activity-of-nanoparticles – present-situati. International Journal of Nanomedicine, 12, 1227–1249. Retrieved from https://www.ncbi.nlm. nih.gov/pmc/articles/PMC5317269/pdf/ijn-­12-­1227.pdf Yeap, S.  P. (2018). Permanent agglomerates in powdered nanoparticles: Formation and future prospects. Powder Technology, 323, 51–59. https://doi.org/10.1016/J.POWTEC.2017.09.042 Yu, T. J., Li, P. H., Tseng, T. W., & Chen, Y. C. (2011). Multifunctional Fe3O4/alumina core/shell MNPs as photothermal agents for targeted hyperthermia of nosocomial and antibiotic-resistant bacteria. Nanomedicine, 6(8), 1353–1363. https://doi.org/10.2217/NNM.11.34 Zare, Y., Rhee, K. Y., & Hui, D. (2017). Influences of nanoparticles aggregation/agglomeration on the interfacial/interphase and tensile properties of nanocomposites. Composites Part B: Engineering, 122, 41–46. https://doi.org/10.1016/j.compositesb.2017.04.008 Zhang, T., He, P., Guo, D., Chen, K., Hu, Z., & Zou, Y. (2023). Research progress of aluminum phosphate adjuvants and their action mechanisms. Pharmaceutics, 15(6), 1756. https://doi. org/10.3390/pharmaceutics15061756

Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications Rishikesh Kumar, Namrata Kumari, and Ganesh C. Sahoo

Introduction Nanoparticles (NPs) that possess magnetic properties are referred to as magnetic nanoparticles and they can be manipulated by external magnetic fields for myriad applications (Aisida et al., 2019a, b, c; Wilczewska et al., 2012). The most common biomedical applications include fluorescence (Bruchez et  al., 1998; Parak et  al., 2003), drug delivery (Cao et  al., 2008; Mah et  al., 2002), contrast enhancement magnetic resonance imaging (MRI) (Hola et al., 2015), nanobots (Douglas et al., 2012, Farahani & Farahani, 2016), hyperthermia (Aisida et al., 2021), bio-detection (Mah et al., 2002), antimicrobial activities (Aisida et al., 2020a, b, c, d, detection of proteins (Nietzold & Lisdat, 2012), tissue engineering (Salata, 2004), phagokinetic studies (Parak et al., 2002), and wound healing (Park et al., 2009; Takei et al., 2012). They consist of two components: a magnetic material (usually iron (Fe), nickel (Ni), or cobalt (Co)) and a functional chemical material. However, metallic magnetic nanoparticles have a higher magnetic moment and good saturation magnetization. Their oxides, such as maghemite and magnetite, are more suitable for biomedical applications (Aisida et al., 2019a, b, c). The method of synthesizing MNPs is important as it determines the size, shape, surface properties, and their applications. Iron oxides can exist in various polymorphs (Madubuonu et  al., 2019; Aisida et  al., 2019a, b, c, 2020a, b, c, d). Magnetic iron oxide nanoparticles (MNPs) are usually functionalized with proteins (amino group), silica, polymer, surfactants, and organic R. Kumar (*) · N. Kumari Department of Microbiology, Molecular/Drug Delivery Lab, Indira Gandhi Institute of Medical Science Patna, Patna, Bihar, India G. C. Sahoo Department of Microbiology, Nanomedicine/Virology Lab, Rajendra Memorial Research Institute of Medical Science Patna, Patna, Bihar, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_13

289

290

R. Kumar et al.

materials to reduce toxicity and optimally fulfil their biomedical functions in drug delivery applications. The non-functionalized iron oxides generally undergo degradation and leaching; hence, they are not biocompatible and agglomerate easily owing to the magnetic dipole-dipole attraction that upshots to poor stability and dispersity. Hence, their usability is limited (Aisida et al., 2019a, b, c). The colloidal suspension of iron oxides (unfunctionalized), particularly magnetite, is easily oxidized in air and susceptible to loss of magnetism. The dispersibility of iron oxides in a biological system can be enhanced by functionalizing the materials using organic and inorganic surfactants, such as biopolymers (such as nucleic and citric acids, albumin, collagen, dextran, chitosan, alginate, starch, chitin, lignin, gelatin, ethyl cellulose, and liposomes) (Aisida et al., 2019a, b, c). Some synthetics polymers, such as polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and polyethylene glycol (PEG), can also be used to enhance the functionalization of iron oxides nanoparticles (Aisida et  al., 2019a, b, c). Magnetic nanoparticles often display a range of particle sizes and morphologies as a result of the nucleation and crystal growth that occurs during synthesis (Khan et al., 2011). The particle size, morphology, and magnetic properties of iron oxide nanoparticles often influence their biomedical applications. Different synthesis routes such as “top-down” and “bottom-up” are employed by different researchers to define the particle size, morphology, and magnetic properties of iron oxide. Top-down major methods are pulsed laser ablation, laser ablation (Sylvestre et al., 2004), aerosol spray pyrolysis (Kastrinaki et al., 2018), sputtering (Couture et al., 2017), and gas-phase deposition. These synthesis routes are often difficult due to the setup mechanism and not easily scaled up. The “bottom-up” methods, such as hydrothermal method (Khalil et al., 2014), coprecipitation, solvothermal method (Mahltig et al., 2009), microemulsion (Cozzoli et al., 2004), and sol-gel method, are the most common. The nanoparticles formed from these methods are efficient, and the composition of size and shape are easily controlled, but they are chemically enhanced and not biocompatible for biomedical applications. But the “bottom-up” synthesis route through biosynthesis and the green synthesis route are facile, efficient, eco-friendly, biocompatible, and easily scaled up (Aisida et al., 2019a, b, 2020a, b, c, d). In recent times, infectious diseases have become a great burden on the world economy as well as on public health. Various health issues, including chronic obstructive pulmonary disease (COPD), meningitis, human immunodeficiency virus (HIV), inflammatory bowel disease (IBD), severe acute respiratory syndrome (SARS), H5N1, trichomoniasis, and pneumocystis pneumonia are generally caused by microbes, which cause death to millions of people around the world annually. Iron oxide nanoparticles provide a golden platform to modify and develop the properties of pure metals by converting them into their nano forms (nanoparticles), which has applications in antiviral activity and iron oxide nanoparticles represent a novel challenge for the treatment of COVID-19 infection. The unique nature of iron oxide nanoparticles has been exploited in the broad antiviral activity of COVID-19. Recently, an iron oxide nanoparticle has shown antiviral activity of H1N1 virus (Kumar et al., 2019). This chapter provides a detailed insight into the antiviral activity, antibacterial activity, and the toxicity of iron oxide nanoparticles in biological systems using prokaryotes

Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications

291

(Gram-positive and Gram-negative bacteria), eukaryotes (Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, Zebrafish, Murine) organisms, and cell lines. To our knowledge, no review has discussed iron oxide nanoparticles from the afore-mentioned models analyzing them from similar perspectives (i.e., antibacterial and toxicity). We also look at the current advances and functionalization of iron oxide for biomedical applications.

The Biological Activities of MNPs and Mechanism of Action The biological activities of MNPs involve the interaction of nanoparticles with living cells and their effect. This may enhance the function of the cells by promoting the catalytic activity of enzymes or inhibiting an enzyme, which may improve or be detrimental to the performance of the cell, leading to malfunction or cell death. For instance, the interaction of some nanoparticles with the cell membrane of certain cells could lead to the disruption of the integrity of the lipid moieties of the membrane, such that there is a compromise. This prevents it from maintaining its ability to protect the cell and control the traffic of molecules in and out of the cell. The biological activities of MNPs and their related mechanism of action will be discussed in detail in the upcoming sections.

Antimicrobial Activity The antimicrobial activities of iron oxide nanoparticles are important in the fields of genetic and neuron toxicology. In the following subsections, the mechanism of iron oxide nanoparticles’ antibacterial activity in prokaryotes and eukaryotes model organisms is discussed.

Mechanism of Iron Oxide Nanoparticles’ Antiviral Activity The antiviral activity of the iron oxide NPs was determined from the decreased ratio of viral suspensions after treatment with the iron oxide NPs. Antiviral activity of iron oxide showed that higher inhibition at a lower dose may be due to the small size easily interacting with the virus and the regular spatial arrangement of the attached nanoparticles, the center-to-center distance between nanoparticles, and the fact that the exposed sulfur-bearing residues of the protein knobs would be attractive sites for nanoparticle interaction suggest that nanoparticles interact with the virus via preferential binding to the protein knobs of influenza virus. Due to this interaction, nanoparticles inhibit the virus from binding to host cells, as demonstrated in vitro (Mahltig et al., 2009). Although the antiviral mechanism of the composites remains

292

R. Kumar et al.

Fig. 1  At 24 hpi with H1N1-PR8 (at 1.0moi), an 100-fold reduction in viral nanoparticles transcript was observed in the presence of Iron Oxides nanoparticles (07 pg) (Kumar et al., 2019)

to be investigated, the experimental results showing the relationship between antiviral activity and the concentration of iron oxide NPs suggest that the virion and composites interacted (Fig. 1). The molecular mechanism may be a reaction of iron oxide with sulfhydryl group of proteins in the cell inactivating the proteins (Kumar et al., 2019). However, it remains to clarify whether and how the nanoparticles upset the function of membranes. The effect of nanoparticles on important cellular mechanism, like the synthesis of DNA, RNA, and proteins, needs to be addressed. Consequently, detailed studies of the antiviral mechanism of the. iron oxide NPs could lead to the development of practical iron oxide NPs-­ containing materials that will reduce concerns about the risks of diffusion of iron oxide NPs into the surrounding area of infection (Elechiguerra et al., 2005; Kumar et al., 2019). Magnetic Fe3O4 nanospheres have the advantages of uniform particle size distribution, large specific surface area, easy modification, good water solubility, strong dispersion, and excellent magnetism, so it is an ideal carrier material with good separation effect. Quantum dot is an excellent fluorescent material, which has the characteristics of broad excitation range, narrow emission spectra, high fluorescent quantum yield, large molar extinction coefficient, and superior brightness and durability to photobleaching. Furthermore, because of the doping of a large number of quantum dots, the stability and fluorescence intensity of quantum dot nanobeads (QBs) are significantly higher than those of quantum dots, which can effectively improve the sensitivity of the detection method (Elechiguerra et al., 2005; Kumar et  al., 2019). Thus, it would be a good choice to establish a fluorescence-linked

Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications

293

immunosorbent assay (FLISA) based on magnetic Fe3O4 nanospheres and QBs to detect human IgG in serum.

Mechanism of Iron Oxide Nanoparticles’ Antibacterial Activity Most metal oxide nanoparticles exhibit bactericidal properties by the reactive oxygen species (ROS) generation (Mahdy et  al., 2012; Aisida et  al., 2020a, b, c, d). Their effectiveness arises from the chemical structure and metal ion release. According to the research by Taylor & Webster (2009), the antibacterial effects of iron oxide nanoparticles on staphylococcus epidermis were described to be dependent on the concentration of the iron oxide nanoparticles. The ROS species include superoxide radicals (H2O2) and singlet oxygen (Touati, 2000). Interactions between ROS species, proteins, or the chemical product and Fe3O2 NPs could be responsible for the antibacterial activity. The Fe ions− react with the ROS species, according to the Fenton equations, to produce free hydroxyl radicals, and subsequently, hydrogen peroxide that intoxicates the bacteria to death (Padmavathy & Vijayaraghavan, 2008). The NPs interaction continues even after the bacteria is dead, thereby producing more hydrogen peroxide to prevent further bacteria activity in that system (Lee et al., 2008). They exhibited strong antibacterial activity against all these species. Moreover, iron oxide NPs are a cost-effective biocide for various applications. The following are the various modes of iron oxide antibacterial activity. Membrane Disruption Nano (zero-valent iron) may be oxidized by intracellular oxygen resulting in oxidative damage via the Fenton reaction. The benefit of its small size permits nano-iron to penetrate the cells through the vulnerable membranes prone to chemical disruption. This consequently leads to physical damage, disruption of cell walls, and variation in morphology. The compromised cells may lose communication with other cells, thus, rendering the cells inactive; therefore, limiting both the growth and multiplication of the microorganism (Ryan et al., 2002). It is, however, possible that the Fe(II) ions released from nano Fe0 contributes to Escherichia coli (E.coli) inactivation by physical damage. However, a significant amount of Fe(II) ions may be transported into the cell by passive diffusion (Ryan et  al., 2002). You et  al. (2005), investigated the inactivation of bacteriophages by iron-based compounds using iron oxide-coated sands. Kim et al. (2021), studied microscale iron powder. However, in both cases, the biocidal activity required a relatively long treatment time, thus, indicating very poor biocidal activities. The bactericidal activity of iron oxide is size-­ dependent; hence, the nanoscale has a strong bactericidal effect than microscale and bulk iron oxide.

294

R. Kumar et al.

Cell Enzymatic Inhibition ROS generated by the presence of iron oxide may lead to the inhibition of pathogenic bacteria. Also, the reduction of iron (with a valency of zero) may affect the enzyme activity in the protein membrane of E coli by electron transfer, but the deactivation mechanisms are still unclear and require further investigations (Lee et al., 2008). Protein and DNA Damage Fe(II) most often induces oxidative stress by generating ROS. The latter is stimulated when intracellular oxygen or hydrogen peroxide is present in the cell (Kim et al., 2001). Arakha et al. (2015), reported that hydrogen peroxide could be generated from Fe2+ response to the presence of oxygen. However, detailed investigations are required to ascertain if the Fe(II) ions are bonded directly to DNA or proteins, which may disrupt cell replication or enzymatic activities.  ntibacterial Activity of Iron Oxide Nanoparticles A in Prokaryotic Organisms The antibacterial activity of metallic nanoparticles of silver (Ag), zinc (Zn), and manganese (Mn) has been extensively discussed in the literature. In this section, we focus on iron oxide nanoparticles. Antibacterial activity is reported to be higher in positively charged iron oxide nanoparticles than the negatively charged ones (Liakos et  al., 2014). This effect could be explained by the interaction between the negatively charged iron oxide nanoparticles and bacteria, thereby creating a repulsive electrostatic field at the interface. The latter prevents the NPs from attaching to the bacterial cell. Nevertheless, at high NPs concentration, they show significant activity, which suggests that ROS was produced. Therefore, the antibacterial activity of the nanoparticles depends on the charge of the iron oxide and the sensitivity of the bacteria. Iron oxides, in the bulk form, are deficient in microbial activities (Prabhu et al., 2015). However, at the nanoscale, they may exhibit some level of antimicrobial activity. A novel surfactant, Tween-80 (it avoids the agglomeration), was used to synthesize MNPs with urea fuel, which revealed that Fe3O4 with a size of about 35 nm had antibacterial properties on both gram-positive and gram-negative bacterial strains, with high zone inhibition. More so, the cell wall and outer membrane of E. coli have been altered by iron oxide nanoparticles (Foriel et al., 2015).  ntibacterial Activity of Iron Oxide Nanoparticles A in Eukaryotic Organisms Eukaryotic organisms, such as yeast (Saccharomyces), Drosophila, Caenorhabditis elegans (C. elegans), zebrafish, and mouse (Chakraborty et al., 2016), among others, are frequently used to elucidate the regulatory mechanisms involved, such as

Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications

295

complex protein communication or signal-transduction pathway and responses to external influences (Fernandes et al., 2015; Pastuhov et al., 2015). With these models, the disease state caused by external influences can be accounted for to a great extent. The antimicrobial activity of iron oxide nanoparticles on eukaryotic models are discussed in the following sections. Saccharomyces cerevisiae Saccharomyces cerevisiae (S. cerevisiae) is an abundant ascomycete yeast commonly used in the food industry. S. cerevisiae can be identified by their morphology, growth, and biochemical studies. It is also a common probiotic in humans, though it is responsible for some infections. Sasakura and Mori (2013), discussed the essence of magnetic nanoparticles in preventing fungal biofilms. They introduced fatty acid-functionalized magnetite nanostructures into a culture media containing S. cerevisiae strain, as an experimental model for studying in vitro microbial biofilms on different substrata. Their result showed that magnetite nanoparticles coated with oleic acid have a strong fungicidal potential than the uncoated surfaces (He et al., 2011). Caenorhabditis elegans Caenorhabditis elegans (C. elegans) are a free-living nematode, whose habitat is the soil ecosystem. It has been established that C. elegans can be used as a model organism for a countless variety of genetic investigations; it is specifically helpful in studying biological systems. C. elegans exhibits behaviors that reflect learning and memory (Martinez et al., 2011). C. elegans are an excellent model to examine the effect of magnetic nanoparticles in drug delivery at the molecular level, cellular, and whole organism. They are also used in the study of metal oxide toxicity and metal homeostasis (Klang et al., 2014). However, exposing cells to a high dose of iron oxide NPs results in the formation of excess ROS, which affects the normal cells with corresponding apoptosis or cell death. Metals like Fe, Zn, Mg, etc., negatively impact certain genes associated with age-related protein and longevity, hence, may be detrimental. In addition, the alteration in the concentration of various metals (e.g., Fe, Mn, Cu, and Zn) in the in vitro growth media results in delayed development, low fertility, abnormal features, and reduction in life span (Chen et al., 2015). Drosophila melanogaster The dyshomeostasis of Fe affects the female Drosophila than the male. This is associated with the decrease in the female fecundity, delay in the larva-pupa development, and in pupa-adult transitions. This phenomenon was observed mainly in Drosophila treated with iron oxide nanoparticles (IONPs) coated with positive

296

R. Kumar et al.

3-aminopropyltriethoxylsilane (Chifiriuc et al., 2016). The mechanism of the reduction of female fecundity can be attributed to the ability of NPs to penetrate through and into the ooplasm and vitelline membrane of Drosophila eggs. Also, the parental uptake on MNPs alters the oogenesis period, thereby inducing an ovarian defect, which lowers the number of nurse cells, diminishes the length of the egg, and retards the egg chamber development (Montazerolghaem et al., 2015). This was confirmed in work by Chifiriuc et al. (2016) and Iguchi et al. (2015), where they studied the effects of magnetite (Fe3O4) NPs capped, modified, and coated with pristine citric acid and 3-aminopropyltriethoxylsilane in concentrations of 300–600  μg/mL.  To investigate the activation of the immune system due to foreign stimuli, hemolymph cells were used. It was shown that their immune response could be activated by hemolymph composition, DNA damage, and larval viability, after treatment with 500  ppm and 1000  ppm chitosan-coated magnetite nanoparticles for 24  h. They showed that the activation of cellular immune response after exposure to the nanoparticles might be attributed to the increase of hemocytes with the emergence of lamellocytes and the presence of apoptotic hemocytes. However, there was no DNA damage at 500 ppm of chitosan-coated magnetite nanoparticles. On the other hand, cellular toxicity was observed in 1000 ppm concentration along with correspondingly low larvae viability.

Toxicity Analysis of Iron Oxide Nanoparticles Toxicology is the study of the adverse effects of chemical, physical, and biological agents on humans, animals, and the environment. Toxicity in cells leads to weakened mitochondrial activity, membrane leakage, and morphological changes. On the other hand, toxic MNPs can adversely affect cell viability, proliferation rate, and metabolic activity and distort the therapeutic efficiency of the treatment (Yang et al., 2011). The toxicity of MNPs on biological entities fundamentally depends on the characteristics of the MNPs, dose, and applications (Huang et al., 2008). Magnetite nanoparticles are generally nontoxic and proven to prevent protein aggregation (Bellova et al., 2010). Toxicological investigation of novel nanomaterials is a major developmental step towards their clinical approval.

Routes of Exposures and Toxicity of Magnetite Nanoparticles Exposure to magnetite particles can occur even in our ambient environment. In a study, rats were exposed to iron oxide dust, and they showed no mortality, no change in body weight, food and water consumption, or any systemic toxicity (Pauluhn, 2012). In another study, subway particles majorly containing iron oxide were found to be toxic. Though magnetite particles in themselves have no toxic effect, other compounds in the dust were the cause of the toxicity (Karlsson et  al., 2008).

Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications

297

Ultrafine particles can enter the body through skin pores, debilitated tissues, injection, olfactory, respiratory, and intestinal tracts. This exposure to media could be intentional or unintentional. Some experimentally identified routes of nanomaterials into the body include pharyngeal instillation, injection, inhalation, cell lines, and gavage exposures, of which inhalation is the major entry route of NPs. The accumulation of IONPs may result in apoptosis as it alters the function of the macrophages. Shen et al. (2011), reported that the exposure of IONPs to murine macrophage cell line J774 caused apoptosis due to increased intracellular ROS.  The latter can be formed when the magnetite is exposed to toxic solutions as a result of oxidation of either structural Fe2+ at the Fe3O4 surface or from the solution (Auffan et al., 2008). The Fenton equations show the production of ROS; Fenton process involves the reaction of hydrogen perox-ide with ferrous salt to formhydroxyl radicals through a Haber–Weiss mechanism, under acidic conditions (pH  -3), according to Eqs. (1) and (2) (Hou et al., 2015).

Fe2 + + H 2 O2 → Fe3+ + OH − + • OH k1 = 76 M −1 s −1 (1)



Fe3+ + H 2O2 → Fe2 + + H + + HO2 • 0.001 ≤ k2 ≤ 0.01M −1 s −1 (2)

The dominant toxicity of IONPs poses a potential risk, such as inflammation, fibrosis, genotoxicity, and extrapulmonary effects. They are linked with increased oxidative stress. IONPs are also directly or indirectly incorporated into consumer products during the manufacturing process (Kornberg et al., 2017).

 oxicity Evaluation of IONPs Using Prokaryotic T Model Organisms Fe2O3 nanoparticles were tested on prokaryotic using a combination of bacterial cytotoxicity assay and genotoxicity assays. Fe2O3 nanoparticles with mammalian cells showed no cytotoxicity or genotoxicity on cells. S. cerevisiae and E. coli were used to investigate the difference in the toxicity level of MNPs on Eukaryotes and Prokaryotes. At a pH of 10, a small killing effect was observed on E. coli due to low sorption level, while a strong bactericidal effect was seen at pH  4 as described. However, S. cerevisiae showed only just slight changes at both pH levels with respect to the iron oxide concentration (Williams et al., 2006). Auffan et al. studied the toxicity of Fe2O3, γ- Fe2O3, and Fe0 on Gram-negative bacterium, such as E. coli. It showed no cytotoxicity after toxicity study. Therefore, it was concluded that oxidative stress was the main source of toxicity. However, other toxic mediums may account for the disruption of the membrane and disturbance of the electron or ions chain of transport after the adsorption of IONPs on the bacteria wall (Mayne et al., 2018). The toxicity of silica/iron oxide nanoparticles on E. coli was studied by Williams et al. They based their result on the growth process of the bacteria and

298

R. Kumar et al.

reported that E. coli showed no growth inhibition. It was opined that agglomeration leads to sedimentation of the nanoparticles, hence limiting the interaction of the NPs with E. coli (Peng et al., 2018).

 oxicity Evaluation of IONPs Using Eukaryotic T Model Organisms Paramecium caudatum (P. caudatum) cultivated in excess MNPs coated with starch was used to examine its toxicological effects. The results showed that the P. caudatum cell was tolerant to MNPs and had no harmful effect on the organism, regardless of the size, morphology, motility, growth rate, or colony density of the MNPs. It, therefore, suggested that MNPs have no toxic effect on the ciliated model organism (Leung et  al., 2008). The toxic effect of iron oxide nanoparticles on Saccharomyces cerevisiae, and, Caenorhabditis elegans, are discussed in the following sections. Saccharomyces cerevisiae Fe3O4 nanoparticles showed an inhibiting effect on the growth of S. cerevisiae, which was attributed to their interaction with the mitochondria, leading to the interruption of their respiratory chain, reduced membrane potential, and a subsequent decrease of ATP production. The study uncovered the potential toxicity of Fe3O4 nanoparticles to the mitochondria of eukaryotic cells. It was proven that cell death and ROS accumulation were not responsible for growth inhibition (Li et al., 2012). Caenorhabditis elegans C. elegans are interesting for environmental and toxicological studies (Lim et al., 2012) in various nanoparticles. The effect of superparamagnetic iron oxide nanoparticles (SPIONs) on C. elegans by the combination of a genome-wide analysis with citrate (Cit.) and protein (bovine serum albumin (BSA)) molecular markers are usually linked to nanotoxicity. Transcriptional modulation of key signaling pathways was detected as the major contributor to SPIONs toxicity and it controls the response of C. elegans to metal oxide NPs. BSA was reported to act as a biomimetic layer that decreases the dissolution of SPIONs and prevents the interaction of the nanoparticle with the intestinal cells (Choi et al., 2014; Wu et al., 2012). Hence they inhibit the any adverse effect, they may have on C. elegans. The safety of various concentrations of Fe2O3-NPs in nematode C. elegans was obtained by studying their toxicity, development, reproduction, locomotion behavior, pharyngeal pumping, defecation, intestinal autofluorescence, and ROS production. After the treatment of C. elegans (larvae and adult) with Dimercaptosuccinic acid (DMSA), the coated

Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications

299

Fe2O3-NPs changed their locomotion behaviors and ROS production. The toxicity observed in the nematodes was due partly but not limited to the formation of oxidative stress (Handy et al., 2012). Future perspectives of MNPs have promising applications in medicine, such as targeted drug delivery, hyperthermia for cancer therapy, contrast agent in magnetic resonance imaging, and antimicrobial, but require various improvements: advancement in technology can help promote the study of functional MNPs and increase their efficiency (Hoss et al., 2015). The development of accurate targeting and remote control of the MNPs to the tumor site to either release the drug load or destroy the tumors is important (Almeida et al., 2011). To improve the biocompatible MNPs, a better understanding of nanoparticles on specific tissues, cells, distribution, and clearance that can cause potential toxicity or adverse effects on system activity is required.

Conclusion Magnetic nanoparticles generally undergo degradation and leaching; hence, they are not biocompatible and agglomerate easily owing to the magnetic dipole-dipole attraction that upshots to poor stability and dispersity, which limit their usability. The colloidal suspension of magnetic nanoparticles without surface architecture is easily oxidized in air and susceptible to loss of magnetism. The dispersibility of magnetic nanoparticles in a biological system can be enhanced by functionalizing the materials using organic and inorganic coating agents such as biopolymers and extract from plants. The toxicity of magnetic nanoparticles depends on so many factors, such as coating, synthesis method, physiochemical, physiological properties, and concentration (dose), which need to be considered when using them for biomedical or physiological purposes. In this work, iron oxide nanoparticles were exploited in different model organisms ranging from prokaryotes to eukaryotes, elucidating their cellular functions relative to their antiviral activity, antibacterial activity, drug delivery, and toxicity. Declaration of Interests  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding  No funding was obtained for this work. The authors declare that they have no competing interests.

References Aisida, S. O., Ugwu, K., Akpa, P. A., Nwanya, A. C., Ejikeme, P. M., Botha, S., et al. (2019a). Biogenic synthesis and antibacterial activity of controlled silver nanoparticles using an extract of Gongronema Latifolium. Materials Chemistry and Physics, 237, 121859. Aisida, S. O., Ugwoke, E., Uwais, A., Iroegbu, C., Botha, S., Ahmad, I., et al. (2019b). Incubation period induced biogenic synthesis of PEG enhanced Moringa oleifera silver nanocapsules and its antibacterial activity. Journal of Polymer Research, 26, 1–11.

300

R. Kumar et al.

Aisida, S. O., Akpa, P. A., Ahmad, I., Maaza, M., & Ezema, F. I. (2019c). Influence of PVA, PVP and PEG doping on the optical, structural, morphological and magnetic properties of zinc ferrite nanoparticles produced by thermal method. Physica B: Condensed Matter, 571, 130–136. Aisida, S.  O., Madubuonu, N., Alnasir, M.  H., Ahmad, I., Botha, S., Maaza, M., & Ezema, F. I. (2020a). Biogenic synthesis of iron oxide nanorods using Moringa oleifera leaf extract for antibacterial applications. Applied Nanoscience, 10, 305–315. Aisida, S. O., Akpa, P. A., Ahmad, I., Zhao, T. K., Maaza, M., & Ezema, F. I. (2020b). Bio-inspired encapsulation and functionalization of iron oxide nanoparticles for biomedical applications. European Polymer Journal, 122, 109371. Aisida, S.  O., Batool, A., Khan, F.  M., Rahman, L., Mahmood, A., Ahmad, I., et  al. (2020c). Calcination induced PEG-Ni-ZnO nanorod composite and its biomedical applications. Materials Chemistry and Physics, 255, 123603. Aisida, S.  O., Ahmad, I., & Ezema, F.  I. (2020d). Effect of calcination on the microstructural and magnetic properties of PVA, PVP and PEG assisted zinc ferrite nanoparticles. Physica B: Condensed Matter, 579, 411907. Aisida, S.  O., Ali, A., Oyewande, O.  E., Ahmad, I., Ul-Hamid, A., Zhao, T.  K., et  al. (2021). Biogenic synthesis enhanced structural, morphological, magnetic and optical properties of zinc ferrite nanoparticles for moderate hyperthermia applications. Journal of Nanoparticle Research, 23, 1–14. Almeida, J. P. M., Chen, A. L., Foster, A., & Drezek, R. (2011). In vivo biodistribution of nanoparticles. Nanomedicine, 6(5), 815–835. Arakha, M., Pal, S., Samantarrai, D., Panigrahi, T. K., Mallick, B. C., Pramanik, K., et al. (2015). Antimicrobial activity of iron oxide nanoparticle upon modulation of nanoparticle-bacteria interface. Scientific Reports, 5(1), 14813. Auffan, M., Achouak, W., Rose, J., Roncato, M., Chanéac, C., Waite, D., Masion, A., Woicik, J.  C., Wiesner, M.  R., & Bottero, J.  Y. (2008). Relation between the redox state of iron-­ based nanoparticles and their cytotoxicity toward Escherichia coli. Environmental Science & Technology, 42(17), 6730–6735. Bellova, A., Bystrenova, E., Koneracka, M., Kopcansky, P., Valle, F., Tomasovicova, N., & Gazova, Z. (2010). Effect of Fe3O4 magnetic nanoparticles on lysozyme amyloid aggregation. Nanotechnology, 21(6), 065103. Bruchez, M., Jr., Moronne, M., Gin, P., Weiss, S., & Alivisatos, A. P. (1998). Semiconductor nanocrystals as fluorescent biological labels. Science, 281(5385), 2013–2016. Cao, S. W., Zhu, Y. J., Ma, M. Y., Li, L., & Zhang, L. (2008). Hierarchically nanostructured magnetic hollow spheres of Fe3O4 and γ-Fe2O3: Preparation and potential application in drug delivery. The Journal of Physical Chemistry C, 112(6), 1851–1856. Chakraborty, C., Sharma, A. R., Sharma, G., & Lee, S. S. (2016). Zebrafish: A complete animal model to enumerate the nanoparticle toxicity. Journal of Nanobiotechnology, 14(1), 1–13. Chen, H., Wang, B., Feng, W., Du, W., Ouyang, H., Chai, Z., & Bi, X. (2015). Oral magnetite nanoparticles disturb the development of Drosophila melanogaster from oogenesis to adult emergence. Nanotoxicology, 9(3), 302–312. Chifiriuc, M. C., Ratiu, A. C., Popa, M., & Ecovoiu, A. A. (2016). Drosophotoxicology: An emerging research area for assessing nanoparticles interaction with living organisms. International Journal of Molecular Sciences, 17(2), 36. Choi, J., Tsyusko, O. V., Unrine, J. M., Chatterjee, N., Ahn, J. M., Yang, X., et al. (2014). A micro-­ sized model for the in vivo study of nanoparticle toxicity: What has Caenorhabditis elegans taught us? Environmental Chemistry, 11(3), 227–246. Couture, P., Williams, G. V. M., Kennedy, J., Leveneur, J., Murmu, P. P., Chong, S. V., & Rubanov, S. (2017). Multiferroic nanocrystalline BiFeO3 and BiCrO3 thin films prepared by ion beam sputtering. International Journal of Nanotechnology, 14(1–6), 56–65. Cozzoli, P.  D., Comparelli, R., Fanizza, E., Curri, M.  L., Agostiano, A., & Laub, D. (2004). Photocatalytic synthesis of silver nanoparticles stabilized by TiO2 nanorods: A semiconductor/ metal nanocomposite in homogeneous nonpolar solution. Journal of the American Chemical Society, 126(12), 3868–3879.

Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications

301

Douglas, S. M., Bachelet, I., & Church, G. M. (2012). A logic-gated nanorobot for targeted transport of molecular payloads. Science, 335(6070), 831–834. Elechiguerra, J.  L., Burt, J.  L., Morones, J.  R., Camacho-Bragado, A., Gao, X., Lara, H.  H., & Yacaman, M.  J. (2005). Interaction of silver nanoparticles with HIV-1. Journal of Nanobiotechnology, 3, 1–10. Farahani, A., & Farahani, A. (2016). An adaptive controller for motion control of nanorobots inside human blood vessels. Bioscience Biotechnology Research Communications, 9(3), 546–552. Fernandes, V.  M., Pradhan-Sundd, T., Blaquiere, J.  A., & Verheyen, E.  M. (2015). Ras/MEK/ MAPK-mediated regulation of heparin sulphate proteoglycans promotes retinal fate in the Drosophila eye–antennal disc. Developmental Biology, 402(1), 109–118. Foriel, S., Willems, P., Smeitink, J., Schenck, A., & Beyrath, J. (2015). Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. The International Journal of Biochemistry & Cell Biology, 63, 60–65. Handy, R. D., Cornelis, G., Fernandes, T., Tsyusko, O., Decho, A., Sabo-Attwood, T., et al. (2012). Ecotoxicity test methods for engineered nanomaterials: Practical experiences and recommendations from the bench. Environmental Toxicology and Chemistry, 31(1), 15–31. He, S., Feng, Y., Gu, N., Zhang, Y., & Lin, X. (2011). The effect of γ-Fe2O3 nanoparticles on Escherichia coli genome. Environmental Pollution, 159(12), 3468–3473. Hola, K., Markova, Z., Zoppellaro, G., Tucek, J., & Zboril, R. (2015). Tailored functionalization of iron oxide nanoparticles for MRI, drug delivery, magnetic separation and immobilization of biosubstances. Biotechnology Advances, 33(6), 1162–1176. Höss, S., Fritzsche, A., Meyer, C., Bosch, J., Meckenstock, R. U., & Totsche, K. U. (2015). Sizeand composition-dependent toxicity of synthetic and soil-derived Fe oxide colloids for the nematode Caenorhabditis elegans. Environmental Science & Technology, 49(1), 544–552. Hou, B., Han, H., Jia, S., Zhuang, H., Xu, P., & Wang, D. (2015). Heterogeneous electro-Fenton oxidation of catechol catalyzed by nano-Fe3O4: Kinetics with the Fermi’s equation. Journal of the Taiwan Institute of Chemical Engineers, 56, 138–147. Huang, D. M., Chung, T. H., Hung, Y., Lu, F., Wu, S. H., Mou, C. Y., et al. (2008). Internalization of mesoporous silica nanoparticles induces transient but not sufficient osteogenic signals in human mesenchymal stem cells. Toxicology and Applied Pharmacology, 231(2), 208–215. Iguchi, Y., Michiue, H., Kitamatsu, M., Hayashi, Y., Takenaka, F., Nishiki, T.  I., & Matsui, H. (2015). Tumor-specific delivery of BSH-3R for boron neutron capture therapy and positron emission tomography imaging in a mouse brain tumor model. Biomaterials, 56, 10–17. Karlsson, H.  L., Holgersson, Å., & Möller, L. (2008). Mechanisms related to the genotoxicity of particles in the subway and from other sources. Chemical Research in Toxicology, 21(3), 726–731. Kastrinaki, G., Lorentzou, S., Karagiannakis, G., Rattenbury, M., Woodhead, J., & Konstandopoulos, A. G. (2018). Parametric synthesis study of iron based nanoparticles via aerosol spray pyrolysis route. Journal of Aerosol Science, 115, 96–107. Khalil, M., Yu, J., Liu, N., & Lee, R.  L. (2014). Hydrothermal synthesis, characterization, and growth mechanism of hematite nanoparticles. Journal of Nanoparticle Research, 16, 1–10. Khan, F., Khattak, N. S., Khan, U. S., & Rahman, A. (2011). Historical development of magnetite nanoparticles synthesis. Journal of the Chemical Society of Pakistan, 33(6), 793. Kim, D. K., Zhang, Y., Kehr, J., Klason, T., Bjelke, B., & Muhammed, M. (2001). Characterization and MRI study of surfactant-coated superparamagnetic nanoparticles administered into the rat brain. Journal of Magnetism and Magnetic Materials, 225(1–2), 256–261. Klang, I. M., Schilling, B., Sorensen, D. J., Sahu, A. K., Kapahi, P., Andersen, J. K., et al. (2014). Iron promotes protein insolubility and aging in C. elegans. Aging (Albany NY), 6(11), 975. Kornberg, T.  G., Stueckle, T.  A., Antonini, J.  M., Rojanasakul, Y., Castranova, V., Yang, Y., & Rojanasakul, L.  W. (2017). Potential toxicity and underlying mechanisms associated with pulmonary exposure to iron oxide nanoparticles: Conflicting literature and unclear risk. Nanomaterials, 7(10), 307.

302

R. Kumar et al.

Kumar, R., Nayak, M., Sahoo, G.  C., Pandey, K., Sarkar, M.  C., Ansari, Y., et  al. (2019). Iron oxide nanoparticles based antiviral activity of H1N1 influenza A virus. Journal of Infection and Chemotherapy, 25(5), 325–329. Lee, C., Kim, J. Y., Lee, W. I., Nelson, K. L., Yoon, J., & Sedlak, D. L. (2008). Bactericidal effect of zero-valent iron nanoparticles on Escherichia coli. Environmental Science & Technology, 42(13), 4927–4933. Leung, M.  C., Williams, P.  L., Benedetto, A., Au, C., Helmcke, K.  J., Aschner, M., & Meyer, J.  N. (2008). Caenorhabditis elegans: An emerging model in biomedical and environmental toxicology. Toxicological Sciences, 106(1), 5–28. Li, Y., Yu, S., Wu, Q., Tang, M., Pu, Y., & Wang, D. (2012). Chronic Al2O3- nanoparticle exposure causes neurotoxic effects on locomotion behaviors by inducing severe ROS production and disruption of ROS defense mechanisms in nematode Caenorhabditis elegans. Journal of Hazardous Materials, 219, 221–230. Liakos, I., Grumezescu, A. M., & Holban, A. M. (2014). Magnetite nanostructures as novel strategies for anti-infectious therapy. Molecules, 19(8), 12710–12726. Lim, D., Roh, J. Y., Eom, H. J., Choi, J. Y., Hyun, J., & Choi, J. (2012). Oxidative stress-related PMK-1 P38 MAPK activation as a mechanism for toxicity of silver nanoparticles to reproduction in the nematode Caenorhabditis elegans. Environmental Toxicology and Chemistry, 31(3), 585–592. Madubuonu, N., Aisida, S. O., Ali, A., Ahmad, I., Zhao, T. K., Botha, S., et al. (2019). Biosynthesis of iron oxide nanoparticles via a composite of Psidium guavaja-Moringa oleifera and their antibacterial and photocatalytic study. Journal of Photochemistry and Photobiology B: Biology, 199, 111601. Mah, C., Fraites, T. J., Zolotukhin, I., Song, S., Flotte, T. R., Dobson, J., et al. (2002). Improved method of recombinant AAV2 delivery for systemic targeted gene therapy. Molecular Therapy, 6(1), 106–112. Mahdy, S. A., Raheed, Q. J., & Kalaichelvan, P. T. (2012). Antimicrobial activity of zero-valent iron nanoparticles. International Journal of Modern Engineering Research, 2(1), 578–581. Mahltig, B., Gutmann, E., Reibold, M., Meyer, D. C., & Böttcher, H. (2009). Synthesis of Ag and Ag/SiO2 sols by solvothermal method and their bactericidal activity. Journal of Sol-Gel Science and Technology, 51, 204–214. Martinez-Finley, E.  J., Avila, D.  S., Chakraborty, S., & Aschner, M. (2011). Insights from Caenorhabditis elegans on the role of metals in neurodegenerative diseases. Metallomics, 3(3), 271–279. Mayne, R., Whiting, J., & Adamatzky, A. (2018). Toxicity and applications of internalised magnetite nanoparticles within live Paramecium caudatum cells. BioNanoScience, 8(1), 90–94. Montazerolghaem, M., Nyström, L., Engqvist, H., & Ott, M. K. (2015). Zebrafish: A possible tool to evaluate bioactive ions. Acta Biomaterialia, 19, 10–14. Nietzold, C., & Lisdat, F. (2012). Fast protein detection using absorption properties of gold nanoparticles. Analyst, 137(12), 2821–2826. Padmavathy, N., & Vijayaraghavan, R. (2008). Enhanced bioactivity of ZnO nanoparticles—An antimicrobial study. Science and technology of advanced materials. Parak, W. J., Boudreau, R., Le Gros, M., Gerion, D., Zanchet, D., Micheel, C. M., et al. (2002). Cell motility and metastatic potential studies based on quantum dot imaging of phagokinetic tracks. Advanced Materials, 14(12), 882–885. Parak, W. J., Gerion, D., Pellegrino, T., Zanchet, D., Micheel, C., Williams, S. C., et al. (2003). Biological applications of colloidal nanocrystals. Nanotechnology, 14(7), R15. Park, C.  J., Clark, S.  G., Lichtensteiger, C.  A., Jamison, R.  D., & Johnson, A.  J. W. (2009). Accelerated wound closure of pressure ulcers in aged mice by chitosan scaffolds with and without bFGF. Acta Biomaterialia, 5(6), 1926–1936. Pastuhov, S. I., Hisamoto, N., & Matsumoto, K. (2015). MAP kinase cascades regulating axon regeneration in C. Elegans. Proceedings of the Japan Academy, Series B, 91(3), 63–75.

Iron Oxide-Based Nanoparticles in Modern Antimicrobial and Antiviral Applications

303

Pauluhn, J. (2012). Subchronic inhalation toxicity of iron oxide (magnetite, Fe3O4) in rats: Pulmonary toxicity is determined by the particle kinetics typical of poorly soluble particles. Journal of Applied Toxicology, 32(7), 488–504. Peng, Q., Huo, D., Li, H., Zhang, B., Li, Y., Liang, A., et al. (2018). ROS-independent toxicity of Fe3O4 nanoparticles to yeast cells: Involvement of mitochondrial dysfunction. Chemico-­ Biological Interactions, 287, 20–26. Prabhu, Y. T., Rao, K. V., Kumari, B. S., Kumar, V. S. S., & Pavani, T. (2015). Synthesis of Fe3O4 nanoparticles and its antibacterial application. International Nano Letters, 5, 85–92. Ryan, J. N., Harvey, R. W., Metge, D., Elimelech, M., Navigato, T., & Pieper, A. P. (2002). Field and laboratory investigations of inactivation of viruses (PRD1 and MS2) attached to iron oxide-­ coated quartz sand. Environmental Science & Technology, 36(11), 2403–2413. Salata, O.  V. (2004). Applications of nanoparticles in biology and medicine. Journal of Nanobiotechnology, 2(1), 1–6. Sasakura, H., & Mori, I. (2013). Current opinion in neurobiology. Handbook of Behavioral Neuroscience, 23, 92–99. Shen, C. C., Liang, H. J., Wang, C. C., Liao, M. H., & Jan, T. R. (2011). A role of cellular glutathione in the differential effects of iron oxide nanoparticles on antigen-specific T cell cytokine expression. International Journal of Nanomedicine, 2791–2798. Sylvestre, J. P., Kabashin, A. V., Sacher, E., Meunier, M., & Luong, J. H. (2004). Stabilization and size control of gold nanoparticles during laser ablation in aqueous cyclodextrins. Journal of the American Chemical Society, 126(23), 7176–7177. Takei, T., Nakahara, H., Ijima, H., & Kawakami, K. (2012). Synthesis of a chitosan derivative soluble at neutral pH and gellable by freeze–thawing, and its application in wound care. Acta Biomaterialia, 8(2), 686–693. Taylor, E. N., & Webster, T. J. (2009). The use of superparamagnetic nanoparticles for prosthetic biofilm prevention. International Journal of Nanomedicine, 145–152. Touati, D. (2000). Iron and oxidative stress in bacteria. Archives of Biochemistry and Biophysics, 373(1), 1–6. Wilczewska, A. Z., Niemirowicz, K., Markiewicz, K. H., & Car, H. (2012). Nanoparticles as drug delivery systems. Pharmacological Reports, 64(5), 1020–1037. Williams, D. N., Ehrman, S. H., & Pulliam Holoman, T. R. (2006). Evaluation of the microbial growth response to inorganic nanoparticles. Journal of Nanobiotechnology, 4(1), 1–8. Wu, Q., Li, Y., Tang, M., & Wang, D. (2012). Evaluation of environmental safety concentrations of DMSA coated Fe2O3-NPs using different assay systems in nematode Caenorhabditis elegans. Yang, C. Y., Hsiao, J. K., Tai, M. F., Chen, S. T., Cheng, H. Y., Wang, J. L., & Liu, H. M. (2011). Direct labeling of hMSC with SPIO: The long-term influence on toxicity, chondrogenic differentiation capacity, and intracellular distribution. Molecular Imaging and Biology, 13, 443–451. You, Y., Han, J., Chiu, P. C., & Jin, Y. (2005). Removal and inactivation of waterborne viruses using zerovalent iron. Environmental Science & Technology, 39(23), 9263–9269.

MXene-Based Nanocomposites for Antibacterial Applications Aditya Velidandi, N. Jayarambabu, P. Geetha, and Varaprasad Kokkarachedu

Abbreviations 2D Two-dimensional Ag Silver AMR Antibiotic resistance B. subtilis Bacillus subtilis Cu2+ Copper ions Cu2O Cuprous oxide CuS Copper sulfide E. coli Escherichia coli HCl Hydrochloric acid HF Hydrofluoric acid K. pneumonia Klebsiella pneumoniae MRSA Methicillin-resistant Staphylococcus aureus NIR Near-infrared NPs Nanoparticles P. aeruginosa Pseudomonas aeruginosa P. vulgaris Proteus vulgaris PLGA Poly(lactic-co-glycolic acid) PVA Polyvinyl alcohol PVDF Polyvinylidene fluoride ROS Reactive oxygen species RT Room temperature A. Velidandi (*) Department of Physics, National Institute of Technology, Warangal, Telangana, India N. Jayarambabu (*) Department of Biotechnology, National Institute of Technology, Warangal, Telangana, India P. Geetha Sri Venkateswara College of Engineering Karakam badi, Tirupathi, India V. Kokkarachedu Facultad de Ingeniería, Arquitectura y Diseño, University of San Sebastián, Concepción, Chile © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_14

305

306

S. aureus SEM WHO Wt.%

A. Velidandi et al.

Staphylococcus aureus Scanning electron microscope World health organization Weight percentage

Introduction Antimicrobial resistance (AMR) refers to the ability of microorganisms, such as bacteria, viruses, and fungi, to evolve and become resistant to the drugs that were originally effective in treating them. This phenomenon renders these drugs, including antibiotics, antivirals, and antifungals, less or completely ineffective in controlling infections. AMR poses a significant threat to public health by limiting treatment options, increasing healthcare costs, and potentially leading to more severe and difficult-to-treat infections. It is a global concern that requires coordinated efforts from healthcare professionals, policymakers, researchers, and the public to address and mitigate its impact. The WHO has identified AMR as one of the top ten major threats to global public health (WHO, 2021). In 2016, the United Nations General Assembly’s High-Level Meeting on AMR emphasized the significance of AMR. It urged countries to adopt their own National Action Plans to address it (PRESS RELEASE: High-Level Meeting on Antimicrobial Resistance | General Assembly of the United Nations, 2023). Despite these initiatives, drug-resistant infections led to an alarming 4.95 million deaths worldwide in 2019, primarily affecting low- and middle-income countries, especially in sub-Saharan Africa (Murray et al., 2022). This number far surpasses the annual global death tolls of tuberculosis (1.5 million), malaria (643,000), and HIV/AIDS (864,000). If left unchecked, it is projected that AMR-­ related deaths could rise to 10 million annually by 2050 (Walsh et al., 2023).The causes of AMR are complex, but there is unanimous agreement that excessive antibiotic usage has played a central role. From 2000 to 2015, there was a 65% worldwide surge in antibiotic consumption, largely propelled by a significant rise in low- and middle-income countries (Klein et  al., 2018). Monitoring the trends in antibiotic usage across various nations and throughout time could provide valuable insights for crafting strategies that enhance the appropriate prescription of antibiotics and reduce the development of AMR. Even under an optimistic perspective, if the global approach to AMR is not taken seriously, it could lead to an economic decline of 1.1% of the world’s gross domestic product each year by 2050. However, if no action is taken, this lack of response could escalate the economic consequences to an even more substantial 3.8% decline annually (Patel et al., 2023). Observing the extent of AMR challenges and overseeing the worldwide efforts to combat AMR stand as one of the four key strategic focuses on AMR designated by the WHO. AMR emerges as a consequence of natural evolutionary changes, either brought about by genetic mutations or the acquisition of resistance genes from other microorganisms. These changes can impede the

MXene-Based Nanocomposites for Antibacterial Applications

307

effectiveness of a drug by hindering its absorption, altering its target within the microorganism, rendering it inactive, or actively expelling it from the microorganism’s environment (Reygaert, 2018). Furthermore, the biofilm structures created by bacteria with AMR have played a substantial role in the development of multidrug resistance (Zou et al., 2023). Treating bacteria that are resistant to multiple antibiotics presents greater more significant challenges, as the options for antibiotics are restricted, often necessitating higher dosages. It is imperative to promptly develop alternative and more potent medications to combat AMR (Zou et al., 2023).

Nanotechnology and Nanomedicine Precise administration of medical treatments has long been a sought-after requirement for effectively addressing severe illnesses while minimizing unwanted effects. Nanotechnology offers a potential solution to fulfill this objective. The strategy of utilizing functional nanoparticles to target bacterial surface elements and vascular adhesion molecules is appealing (Zou et al., 2023). However, due to the diversity among individuals and the evolving nature of disease conditions, selecting the ideal targets poses a significant challenge. Nanotechnology and nanomedicine are playing pivotal roles in addressing the global concern of AMR. These fields leverage the unique properties of nanoscale materials and structures to develop innovative strategies for combating the emergence of drug-resistant microorganisms. Nanotechnology involves the manipulation and engineering of materials at the nanoscale, typically on the order of billionths of a meter. Nanomedicine, a subfield of nanotechnology, focuses on utilizing nanoscale materials for medical applications, including diagnostics, drug delivery, and therapy, holding the potential to enhance effectiveness while minimizing adverse effects. Nonetheless, only a limited number of nanomedicines in the process of clinical development have managed to live up to these expectations. Creating antibacterial nanomedicine is essential for addressing obstacles linked to immune system-­driven rapid elimination, along with additional biological barriers like vascular hindrances, diversity, biofilm presence, and limitations in drug uptake. The progress in nanomedicine and nanobiotechnology has led to the creation of a wide range of innovative inorganic nanosystems (Li et al., 2023). Nanomedicine has brought about a revolution in the pharmaceutical and biotechnology sectors (Dash & Kundu, 2023). The distinctive physical and chemical attributes of Nanomaterials have been critical in the rapid, sensitive, and precise detection of microbial diseases (Dash & Kundu, 2023). Moreover, certain inorganic and organic NPs exhibit notable intrinsic antibacterial properties that are seldom observed in their larger forms. Additionally, specific nanomaterials hold the potential to counter antibiotic resistance by disrupting the pathways of resistance (Dash & Kundu, 2023). In particular, nanomaterials have proven to be the ideal selection for combating bacteria, including antibiotic-resistant strains, owing to their mechanical durability, selectivity, and sensitivity (He et al., 2023). Moreover, nanoparticle designed

308

A. Velidandi et al.

for delivering antimicrobial drugs manage to overcome resistance while causing fewer adverse effects compared to traditional antibiotics (Rajwar et  al., 2023). Researchers are also exploring the prospect of incorporating multiple antigens onto a single particle to confer protection against multiple diseases. Furthermore, nanoparticles are being investigated as carriers for vaccines, exploring nontraditional administration methods such as topical, inhalational, or optical delivery (Mehrabi et al., 2023). Overall, the integration of nanotechnology and nanomedicine into efforts against AMR holds the potential to transform the way integrating nanotechnology and nanomedicine into efforts against AMR can transform how we diagnose, prevent, and treat drug-resistant infections, addressing a critical global health challenge.

Emergence of MXenes 2D nanomaterials, characterized by their substantial lateral dimensions and ease of surface functionalization, exhibit excellent interactions and efficiency in processes such as adsorption, sensing, catalysis, and interaction with bacteria (He et al., 2023). Generally, this category of 2D materials encompasses graphene, transition metal carbonitrides and carbides, transition metal hydroxides, transitional metal dichalcogenides, and transition metal oxides (Koyappayil et al., 2022). These materials possess a high surface-to-volume ratio, resulting in a high surface-to-volume ratio, producing a broad specific surface area (Velidandi et al., 2020, 2023). Additionally, their layered structures enable the reduction of diffusion pathways, contributing significantly to their enhanced ionic and electrical conductivity. Furthermore, the interlayer spacing permits ion intercalation and energy storage (He et al., 2023). The emergence of MXenes represents a significant development in the field of materials science and nanotechnology. MXenes are a class of 2D materials that exhibit unique properties and have garnered considerable attention for their diverse range of potential applications (Li et al., 2023). MXenes represent the most extensive family of 2D materials currently acknowledged, encompassing over 30 distinct variations that have been recorded and hundreds more explored through computational studies. The extraction process from the A-layer of a MAX phase leaves behind 2D flakes, exposing the initial MXene layer. A group of materials exhibiting multilayer hexagonal structures falls under the category of MAX, where M and X symbolize MXenes, while A signifies an element from the A-group. The relatively weak bond between M and X permits the selective etching of an atom situated between them. As a result, MXenes are crystalline 2D entities with the potential for virtually boundless lateral dimensions but an atomically thin profile (Jung et  al., 2023). Their surface atoms, known as terminations, offer exceptional attributes that have captivated the interest of materials researchers and developers in the field of nanotechnology (Venkateshalu & Grace, 2020).

MXene-Based Nanocomposites for Antibacterial Applications

309

Synthesis of MXenes MXenes are generated through the synthesis of carbides and nitrides of transition metals (Solangi et  al., 2023). The precursor for producing MXenes is the MAX phase (Mn  +  1AXn), which consists of tetragonal carbides or nitrides. This MAX phase serves as the foundation for generating MXenes. In the MAX phase, the bonding between M and X displays a mix of covalent, metallic, and ionic characteristics, whereas the bonding between M and A primarily demonstrates metallic traits (Hao et al., 2022). The term “ene” denotes the material’s two-dimensional nature. The process of obtaining MXenes involves selectively etching the “A” element from the MAX phase (Mn + 1AXn, where n ranges from 1 to 3). This process leads to the chemical formula Mn + 1XnTx, where “A” represents elements from groups 12 to 16 (including Sn, Si, Ge, Al, Ti, Zr, Hf, V, Sc, Nb, Ta, Cr, and Mo), “M” signifies early transition metals from the d-block, “X” represents nitrogen and/or carbon, and “T” indicates surface-terminating groups such as fluorine (-F), hydroxyl (-OH), chlorine (-Cl), and oxygen (=O) (shown in Fig. 1, (Vasyukova et al., 2022)) (Idumah et al., 2021; Mansoorianfar et al., 2022; Solangi et al., 2023). Notably, the bond between “M” and “X” is notably stronger compared to that between “M” and “A” (Solangi et  al., 2023). Additionally, chemical reactivity within the M-X stack is comparatively lower than within the A stacks (Solangi et al., 2023). MXenes can be generated using either top-down or bottom-up techniques (as shown in Table  1). In the top-down approach, MXenes are produced from bulk materials through a two-step process involving chemical etching and subsequent delamination (Xing et al., 2018). In the etching stage, a chemical etchant is employed to break the metallic bond between M and A, leading to the removal of interleaved ‘A’ atom layers from the bulk ceramic structure (George & Kandasubramanian,

Fig. 1  MXenes: (a) Elements that make up MAX and MXenes and (b) production of MXenes through a top-down approach by selectively etching their MAX precursor materials. (Vasyukova et al., 2022)

310

A. Velidandi et al.

2020). The resultant aggregated nanosheets are then delaminated using ultrasonication, tetrapropylammonium hydroxide intercalation, or liquid-phase exfoliation (George & Kandasubramanian, 2020). Conversely, the bottom-up strategy initiates synthesis from individual atoms or molecules, often utilizing chemical vapor deposition techniques (Manawi et al., 2018). Additionally, MXenes can be synthesized via crystal growth, employing small inorganic and organic molecules as precursors (Li et  al., 2023). In contrast to top-down methods, which lack consistent control over reproducibility and size distribution, bottom-up approaches offer the advantage of surface termination, geometric morphology, and precise manipulation of size distribution MXenes (Li et al., 2023). Apart from chemical vapor deposition, salt templates and pulsed laser deposition methods have been developed for MXene preparation (Li et  al., 2023). Following synthesis, various surface terminations, such as -OH, -O, -Cl, and/or -F, are observed (Idumah et al., 2021; Mansoorianfar et al., 2022; Solangi et al., 2023). These terminations confer hydrophilic properties to MXenes and also generate opportunities for surface modifications. In a typical synthetic procedure, the creation of MXenes follows a two-step progression involving the selective removal of A-layer atoms (such as Ga, Si, and Al) from the corresponding MAX phase, followed by the subsequent separation of multilayered MXenes. Following wet chemical etching, loosely stacked MX layers are achieved and can be subsequently disassembled into individual single-layered flakes. Initially, HF is used as the etchant to effectively eliminate the A layers from the MAX phase, generating surface-terminated groups of OH and F. HF etching, widely embraced, serves as an efficient means for quickly etching the MAX phase. Nonetheless, it’s important to acknowledge that HF solutions are remarkably corrosive, hazardous, and prone to causing excessive etching (Tavakolian et al., 2020). Novel etching systems, including HCl/LiF, NH4HF2, and NH4F, have been employed to pursue gentler etching conditions, significantly enhancing the repertoire of synthetic techniques for MXenes (Hao et al., 2022). The incorporation of cations (such as Sn4+, Na+, and Li+) between the Mn + 1Xn layers leads to an expansion in interlayer separations and a reduction in interlayer interactions (Zhang et  al., 2020). Consequently, MXenes nanosheets display fewer defects, larger dimensions, and more uniform thickness.

Properties of MXenes MXenes possess a wide range of properties that make them intriguing for various applications. The specific properties of MXenes can vary based on their composition, structure, and functionalization. Here are some key properties of MXenes: • Electrical conductivity: Many MXenes exhibit high electrical conductivity due to the presence of metallic transition metal layers. This property makes them suitable for applications in electronics, sensors, and energy storage devices.

MXene Ti3C2Tx Ti3C2Tx Mo2Ti2C3Tx Ti2CTx

Ti2NTx

Ti3C2Tx

Nb2CTx Ti3C2Tx Ti2CTx Ti3C2Tx

Mo2C Ti3C2Tx

MAX phase Ti3AlC2 Ti3SiC2 Mo2Ti2AlC3 Ti2AlC

Ti2AlN

Ti3AlC2

Nb2AlC Ti3AlC2 Ti2SC Ti3AlC2

Mo2Ga2C Ti3AlC2

KF (6 g) + HCl (6 M)

Etchants HF (50 wt.%) H2O2 (35 wt.%)/HF (30 wt.%) HF (50 wt.%) LiF (6 M) + HCl (0.9 M)

Miscellaneous

AgCl Algae Thermal reduction strategy Surface acoustic waves, LiF (≈0.05 m) UV light (100 W) I2

Ionic liquid (EMIMBF4/ BMIMPF6) (Nb,Zr)4AlC3 (Nb,Zr)4C3Tx LiF (2.3 M) + HCl (12 M) Alkali etching Ti3AlC2 Ti3C2Tx NaOH (27.5 M) Ti3AlC2 Ti3C2Tx H2SO4(1 M) + NaOH (1 M) Electrochemical etching Ti3AlC2 Ti3C2Tx NH4Cl (1 M) + TMAOH (0.2 M) V2AlC V2CTx HCl (1 M) Molten salt etching Ti2AlC Ti2CTx ZnCl2 Ti2GaC Ti2CTx CuCl2 Ti4AlN3 Ti4N3Tx KF+ LiF+ NaF

In situ HF formation etching

Approach HF etching

Table 1  Various MXenes synthesis approaches (Wei et al., 2021)

3–5 h 100 °C

Ar, 24 h, 700 °C 24 h, RT Ar/H2, 0.5 h, 400–900 °C Millisecond

-O -I, -O,-OH

– -O,-OH -O,-OH -F, -O,-OH

Mei et al. (2020a) Shi et al. (2021)

Pang et al. (2019) Li et al. (2019) Li et al. (2020) Urbankowski et al. (2017) Li et al. (2020) Zada et al. (2020) Mei et al. (2020b) Ghazaly et al. (2021)

-Cl, -O,-OH -Cl, -O -Cl, -O -F, -O

9 h, 50 °C, 0.5 V Ar, 5 h, 550 °C Ar, 24 h, 650 °C Ar, 0.5 h, 550 °C

1 h, 40 °C 20 h, 80 °C, hydrothermal reaction 168 h,50 °C 12 h,270 °C 2 h, 80 °C + 100 h, 80 °C 5 h, 5 V

Surface groups -F, -O,-OH -F, -O,-OH – -F, -O,-OH

Ref. Naguib et al. (2011) Alhabeb et al. (2018) Anasori et al. (2015) Kajiyama et al. (2017) -F, -O,-OH Kajiyama et al. (2017) -F, -O Husmann et al. (2020) – Yang et al. (2016) – Li et al. (2018) -O,-OH Xie et al. (2014) -Cl, -O,-OH Yang et al. (2018)

Etching conditions 2 h, RT 45 h, 40 °C 48 h, RT 15 h, 40 °C

MXene-Based Nanocomposites for Antibacterial Applications 311

312

A. Velidandi et al.

• High surface area: MXenes have a large surface area, often surpassing that of other 2D materials. This property is beneficial for applications in supercapacitors, catalysis, and adsorption-based processes. • Mechanical strength and flexibility: MXenes can possess excellent mechanical properties, including high strength and flexibility. This makes them potential candidates for reinforcement in composite materials and flexible electronics. • Thermal conductivity: MXenes can exhibit good thermal conductivity, which is valuable for applications in thermal management, such as in electronic devices and heat sinks. • Optical properties: Some MXenes have tunable optical properties, including absorption and reflection of light. This makes them useful for applications like photodetectors and optoelectronic devices. • Chemical stability: MXenes are generally stable in a variety of chemical environments, which is crucial for their use in practical applications and integration into various systems. • Surface functionalization: MXenes‘surface functional groups can be modified to tune their properties and enhance their interactions with other materials. Functionalization can also impact their hydrophilicity, stability, and electronic properties. • Biocompatibility: Some MXenes have shown biocompatibility, which opens up possibilities for their use in biomedical applications, such as drug delivery and tissue engineering. • Antimicrobial activity: Certain MXenes have exhibited antimicrobial properties, which can be harnessed for applications in healthcare and materials that require resistance against bacterial growth. • Interlayer spacing: The interlayer spacing between MXene layers can be tuned by introducing different intercalants or functional groups. This property influences ion intercalation and guest molecule adsorption.

Applications of MXenes MXenes, as a growing family of 2D materials, have increasingly attracted a great attention for their potential in various applications, including antibacterial, electromagnetic shields, light-to-heat conversion, energy storage, photoresponse function, photocatalysis, water desalination, etc. (Wang et  al., 2020). MXenes are highly applied in various fields of biomedicine (as shown in Fig.  2) (Koyappayil et  al., 2022). High surface area, the presence of hydrophilic groups, high atomic number, high electrical conductivity, mechanical stability, remarkable visual capabilities, and magnetization behavior patterns are just a few of MXene special qualities (Sana et  al., 2023; Solangi et  al., 2023). The surface area of MXenes are significantly larger than that of other nanostructured materials (Jatoi et al., 2023). MXenes have found applications in every possible field with their 2D structure and unique properties. Here are some notable applications of MXenes:

MXene-Based Nanocomposites for Antibacterial Applications

313

• Energy storage: MXenes are being investigated for use in energy storage devices such as batteries and supercapacitors. Their high electrical conductivity and large surface area make them suitable for electrode materials. MXene-based electrodes can potentially lead to improved energy storage capacity, faster charging/ discharging rates, and longer cycle life in batteries and supercapacitors. • Electromagnetic shielding: The conductivity of MXenes, along with their layered structure, makes them effective materials for electromagnetic interference shielding. They can be used to design lightweight and thin shielding materials for electronic devices, aerospace applications, and communications systems. • Catalysis: MXenes have shown promise as catalysts in various chemical reactions due to their high surface area and tunable electronic properties. They can be used in catalytic processes for applications such as hydrogen evolution, water splitting, and organic synthesis. • Water purification: The hydrophilic nature of some MXenes makes them suitable for water purification and filtration. MXene-based membranes can effectively remove heavy metal ions and other pollutants from water sources, addressing water contamination issues.

Fig. 2  Various applications of MXenes in biomedicine. (Koyappayil et al., 2022)

314

A. Velidandi et al.

• Sensors: MXenes can be used in sensors to detect gases, ions, and biomolecules. Their electrical conductivity can change in response to the presence of specific analytes, enabling the development of highly sensitive and selective sensors. • Flexible electronics: MXenes‘mechanical flexibility and electrical conductivity make them potential candidates for flexible and wearable electronics. They can be integrated into flexible circuits, touch screens, and other electronic components. • Reinforcement in composite materials: MXenes can be incorporated into polymer composites to enhance their mechanical properties, such as strength and stiffness. This makes them valuable for industries like aerospace, automotive, and construction. • Drug delivery: MXenes can serve as carriers for drug delivery due to their large surface area and ability to adsorb molecules. They can protect sensitive drugs during transport and release them in a controlled manner at the desired location. • Transparent conductive films: Some MXenes have the potential to be used as transparent conductive materials in applications like touchscreens, solar cells, and flexible displays. • Antimicrobial coatings: MXenes with inherent antimicrobial properties can be incorporated into coatings for medical devices, surfaces, and textiles to prevent bacterial growth and reduce the risk of infections. • Packaging materials: MXene-based coatings on food packaging materials can help extend the shelf life of products by inhibiting the growth of spoilage microorganisms and pathogens.

In Vitro Antibacterial Properties In an effort to mitigate the health repercussions stemming from the proliferation of microorganisms, a range of 2D materials have been investigated. Notably, MXenes have demonstrated greater antibacterial efficacy compared to graphene and graphene oxide (George & Kandasubramanian, 2020). Mxenes possess unique properties that make them promising materials for antibacterial applications. The high surface area, electrical conductivity, and layered structure enable them to effectively interact with bacterial cells and cause their inactivation. Over the past decade, the potential of MXenes for in vitro antibacterial applications has been extensively validated and has progressed rapidly (Table 2). However, pure MXenes may not consistently fulfil the requirements of antimicrobial treatment due to the development of bacterial resistance over time. To address this issue, complementary approaches like combining MXenes with other antimicrobial agents are being considered as novel strategies (Hao et al., 2022). Combining MXenes with antibiotics are one approach that can enhance the efficacy of antimicrobial treatment. Combining MXenes and antibiotics can reduce the dosage required to achieve the desired antibacterial effect, thereby reducing the risk of antibiotic resistance. Moreover, MXenes can also be combined with other 2D materials (like graphene and graphene oxide), antibacterial polymers (cationic polymers), and inorganic materials to create hybrid materials

MXene-Based Nanocomposites for Antibacterial Applications

315

Table 2  In vitro antibacterial activity of hybrid nanomaterials. examples Type BC/CH/Ti3C2Tx/ AgNWs aerogel V2C Nanosheets

Bacteria S. aureus and E. coli S. aureus and E. coli S. aureus and E. coli

Outcome Showed a nearly 100% sterilizing effect 99.5% bacterial death at 40 μg/ mL concentration Ti3C2Tx/PVA Inhibition rates of 98.3 and hydrogel 95.5%, respectively, were observed Ti3C2Tx MR-S. aureus Size-dependent activity CuP-sTi3C2Tx S. aureus and E. High antibacterial efficiency coli above 99.9% at 5.0 wt.% Ag/Ti3C2Tx S. aureus and E. Exhibited outstanding bacterial coli inhibition Ti3C2Tx-Laden Shigella Reduced 99.99% of the artificial bacteriophage contamination in water samples Ti3AlC2/HACC/PET E. coli 99.99% antibacterial efficiency BC/BaTiO3/MXene S. aureus and E. Excellent photothermal coli antibacterial properties CH/TA/Ti3C2Tx S. aureus and E. Combination enhanced coli antibacterial efficiency CuFe2O4/Ti3C2/PLLA S. aureus and P. 96.49 and 95.33% inhibition aeruginosa after 15 min under NIR irradiation Nb2CTx and Nb4C3Tx B. subtilis and S. Elimination of bacteria during aureus 48 h of incubation Ti3C2/SA/TSA/AM S. aureus and E. >99% inhibition efficiency Hydrogels coli CoFe2O4/HA/ S. aureus and E. Eliminated >99% of bacteria PEGDA/PEEK coli Mo2Ti2C3 MR-S. aureus Showed better efficacy Ti3C2/Au NPs S. aureus Inhibited growth and biofilm development Mo4VC4 MR-S. aureus Caused •OH-induced death

Ref. Fu et al. (2022) Zada et al. (2021) Li et al. (2022)

Gao et al. (2022) Liu et al. (2022) Zhu et al. (2020) Mansoorianfar et al. (2022) Su et al. (2023) Fu et al. (2023) Liu et al. (2023a) Qian et al. (2023)

Wojciechowska et al. (2023) Wu et al. (2023) Wang et al. (2023) Hua et al. (2023) Chen et al. (2023) Liu et al. (2023b)

with enhanced antibacterial properties (Mayerberger et  al., 2018; Rasool et  al., 2016; Seidi et al., 2023). These hybrid materials can leverage the unique properties of each material to create a synergistic effect that enhances their antibacterial efficacy. MXenes have shown great potential for in vitro antibacterial applications due to their unique properties. However, combining MXenes with other antimicrobial agents are a promising approach for enhancing their efficacy and overcoming the limitations of pure MXenes.

316

A. Velidandi et al.

Pure MXenes Due to their remarkable biocompatibility, intriguing antibacterial attributes, and minimal cytotoxicity, MXenes have garnered significant attention for applications in the field of biomedicine (Tavakolian et al., 2020). For instance, Ti3C2Tx, one of the earliest and extensively investigated MXenes, has exhibited exceptional effectiveness, requiring small doses and yielding rapid antibacterial results (Ahamed et  al., 2022; Dong et  al., 2023; Hu et  al., 2022). Employing both few-layered Ti3C2Tx and multilayered Ti3C2Txnanosheets for antibacterial photothermal therapy against E. coli and S. aureus has proven to be feasible. Biocompatibility testing has revealed that certain eukaryotic cell lines exhibited lower cytotoxicity when exposed to few-­layered Ti3C2Tx nanosheets. Additionally, the impact on bacterial cells treated with few-layered Ti3C2Tx was more pronounced, leading to severe damage to cell membranes and content loss, compared to the group treated with multilayered Ti3C2Tx (Rosenkranz et al., 2021). Ti3C2Tx nanosheets have demonstrated potent bactericidal effects against various bacteria, including drug-resistant strains like vancomycin-­ resistant Enterococci and methicillin-resistant Staphylococcus aureus (MRSA) (Wu et al., 2021). Furthermore, this rapid antibacterial approach has the capability to suppress MR-biofilms by disrupting their structures and eradicating the bacteria within. The survival rate of bacteria within the experimental group’s biofilm was notably reduced by 95% compared to the control group (Wu et al., 2021). TiVCTX MXene, possessing antibacterial properties, was synthesized as reported by He et al. (2022). The monolayer variant of TiVCTX exhibited exceptional antibacterial efficacy against B. subtilis and E. coli, with a bactericidal rate exceeding 99.8%. The efficiency of TiVCTX MXene nanosheets in eradicating E. coli arises from the ability of the monolayer’s edges to disrupt cell membranes, leading to the leakage of intracellular substances (He et al., 2022).

MXenes/Other Antimicrobial Agents Combining MXenes with other antimicrobial agents presents a promising avenue to enhance the ability to restrain bacterial reproduction (Hao et al., 2022). Nanoscale Ag holds promise as an antimicrobial agent due to its wide-ranging and enduring antibacterial effectiveness (Khatoon et al., 2023; Vankdoth et al., 2022; Velidandi et al., 2023). An effective strategy involves integrating Ag nanoparticles onto the surface of 2D MXenes to achieve the desired sterilization outcomes (Hao et  al., 2022). In the study conducted by Zhu et al. (2020), Ag+ were initially adsorbed and then subsequently reduced using sodium citrate on negatively charged Ti3C2Tx nanosheets, creating Ag/Ti3C2Tx composites. In the absence of light, an Ag/Ti3C2Tx suspension at a concentration of 200 μg/mL exhibited limited antibacterial activity;

MXene-Based Nanocomposites for Antibacterial Applications

317

however, when subjected to 808 nm NIR light exposure, the composites effectively eradicated all bacteria. The antibacterial tests were consistent with the SEM results, wherein the Ag/Ti3C2Tx composites demonstrated noticeable synergistic antibacterial performance under NIR irradiation. High-resolution imaging clearly illustrated that bacteria exposed to light exhibited leakage of cytoplasm and cellular lysis. The potency of Ag nanoparticles NPs in terms of antimicrobial efficacy is primarily linked to the release of Ag+ (Zhu et al., 2020). CuS is also acknowledged as a widely recognized antibacterial agent due to its remarkable light absorption characteristics and the capability to release Cu2+ (Hao et al., 2022). Recent investigations have pointed to MXenes being well-suited support materials for the creation of nanohybrids, with the surface incorporation of CuS nanoparticles NPs onto them through an in situ growth method emerging as an effective approach (Li et al., 2021). In their work, Li et al. (2021) fabricated MXenes/ CuS composites responsive to NIR light by facilitating a reaction between C2H5NS and Cu2+ absorbed onto the surface of multilayered Ti3C2Tx. This led to the controlled release of Cu2+. Uniformly sized CuS nanoparticles ranging from 100 to 500  nm were successfully cultivated on the surface of multilayered Ti3C2Tx. Capitalizing on the combined photothermal effects of MXenes and CuS, along with the enhanced release of Cu2+ with bactericidal properties, the antibacterial efficacy of the MXenes/CuS composite outperformed 99% against both S. aureus and E. coli (Li et al., 2021). Wang et al. (2020) introduced a novel composite involving Cu2O anchored onto MXene nanosheets. The integration of Cu2O nanospheres onto the MXene surface is achieved with uniformity, owing to the electrostatic interaction between the single-­layer MXene and Cu2O nanospheres. The resulting Cu2O/MXene nanosheet exhibits exceptional antibacterial effectiveness against both P. aeruginosa and S. aureus, with bacteriostasis efficiencies of 97.04% and 95.59%, respectively (Wang et al., 2020). In a study by Warsi et al. (2022), a Tugsten oxide (WO3)/MXene nanocomposite was synthesized by removing an atomic layer of Al from MAX powder, followed by hydrothermal growth of WO3 nanorods. An alternate approach involved the synthesis of WO3/MXene composite through a straightforward sonication method. This WO3/MXene nanocomposite displayed remarkable antibacterial performance against P. vulgaris, K. pneumonia, E. coli, and S. aureus (Warsi et al., 2022). Similarly, Alsafari et  al. (2021) detailed the creation of copper ferrite (CuFe2O4)/MXene nanohybrids using an ultrasonication approach. These hybrids demonstrated exceptional antibacterial activity against a range of bacteria, including K. pneumonia, P. vulgaris, S. aureus, P. aeruginosa, and E. coli surpassing the antibacterial efficacy of individual CuFe2O4 and MXene components (Alsafari et al., 2021). Furthermore, Rasheed et al. (Rasheed et al., 2021) presented a cost-­ effective method for producing nickel ferrite (NiFe2O4)/MXene heterostructures that exhibited notable antibacterial potency, specifically against E. coli.

318

A. Velidandi et al.

MXenes/Polymers Effective polymer surface modifications such as poly(lactic-co-glycolic acid) (PLGA), polyvinyl alcohol (PVA), polyvinylidene fluoride (PVDF), polyvinyl pyrrolidone (PVP), polystyrene S (PS), and PVA, poly(ethylene glycol) PEG, PLGA, among others, have significantly improved the biocompatibility and physiochemical stability of MXenes. These enhancements are achieved through mechanisms like surface adsorption or electrostatic interactions. These modifications have enabled the augmentation of drug loading capacity, target specificity, and biodegradability, rendering MXenes viable for use in various biomedical applications (George & Kandasubramanian, 2020). Rasool et al. (2017) highlighted the antimicrobial potential of Ti3C2Tx supported by PVDF.  Coating the high aspect ratio Ti3C2Tx onto the PVDF membrane led to improved hydrophilicity (with a contact angle of 37°) and a reduction in the presence of large pores within the membrane. This resulted in a significant decrease in the viability and growth inhibition of E. coli (a Gram-negative bacterium) by approximately 73% and B. subtilis (a Gram-positive bacterium) by around 67%. Multiple factors influence the antibacterial efficacy, including the bacterial cell wall structure and environmental conditions. Notably, the thin peptidoglycan layer (2–3 nm) between the outer and inner cell membranes in E. coli and the thicker peptidoglycan layer (20–80  nm) in B. subtilis contribute to the varying resistance rates towards MXenes. Furthermore, altering the thickness of Ti3C2Tx did not lead to significant changes in antibacterial activity, thereby establishing 1.2 μm as the optimal coating thickness for Ti3C2Tx (Rasool et al., 2017). Mayerberg et  al. (2018) introduced a combination of electrospun MXene (Ti3C2Tz) and CH nanofibers designed for antibacterial purposes in biodegradable medical bandages. These nanofibers possess attributes such as a substantial surface area, high porosity, permeability, and absorptivity, making them an excellent medium for incorporating immobilized MXene. Potential interactions between negatively charged MXene functional groups and positively charged nitrogen-­ containing groups in -CH can arise through hydrogen bonding or electrostatic forces. The application of glutaraldehyde crosslinking to the 0.75 wt.% Ti3C2Tz/ CH composite led to a reduction of 95% in E. coli and 62% in S. aureus. The authors concluded that Ti3C2Tz/CH nanofibers are biocompatible and exhibit effective antibacterial properties even at lower concentration , surpassing the performance of other electrospun metal oxide nanoparticles and 2D materials (Mayerberger et al., 2018). A Ti3C2Tx PVA hydrogel was produced by dispersing MXene nanosheets directly into an aqueous PVA solution. To aid in the gelation process, a sodium tetraborate solution was introduced into the mixture as a crosslinking agent. This resulted in the formation of di-diol bonds between the functional groups of the PVA chains. As the gelation occurred, the oxygen-containing surface groups of Ti3C2Tx formed covalent bonds with the B(OH)4−ions and the PVA chains (Zhang et al., 2019).

MXene-Based Nanocomposites for Antibacterial Applications

319

In Vivo Antibacterial Properties The skin, functioning as the body’s largest organ and primary line of defense, maintains internal stability while confronting external threats (He et al., 2020). However, infected wounds on the dermis can lead to pain, amputations, and even fatalities, emerging as a critical global health concern (Yang et al., 2022). Standard wound dressings such as sponges, bandages, and gauze serves to create a physical barrier or absorb exudate, yet they lack the biochemical capacity to eliminate bacteria and facilitate healing (Hao et al., 2022). Zhou et al. (2022) devised a nanoscale catalytic membrane (P-MX/AS@LOx) composed of electrospun PLGA scaffolds, MXenes/ Ag2S (MX/AS) bio-heterojunctions, and lactate oxidase (LOx). The MXenes/Ag2S bio-heterojunctions within the membrane demonstrated a mild photothermal effect and ROS generation under NIR light exposure. Additionally, they effectively neutralized hydroxyl radicals through Fenton-like reactions, leading to a highly effective combined sterilization process. Within 10  min of NIR light exposure, the experimental group’s temperature increased from 22.5 to 61.2 °C, confirming the remarkable efficiency of in vivo photothermal conversion. This nanoscale catalytic membrane transformed stagnant chronic wounds into regenerative wounds by eradicating bacteria, halting bleeding, stimulating angiogenesis, enhancing collagen deposition, and promoting epithelialization (Zhou et al., 2022). In addition to membranes, hydrogels have emerged as a novel class of wound dressings due to their remarkable water-absorbing capacity and porous structure, holding promising potential for advancing wound healing (Hao et  al., 2022). Li et  al. (2022) developed a distinct MXenes@PVA hydrogel using a directional freezing-­assisted salting-out technique. Their investigation utilized a full-thickness S. aureus-infected wound model to assess the efficacy of the MXenes@PVA hydrogel in treating infected skin wounds. Following ten days of treatment, the MXenes@ PVA hydrogel combined with NIR achieved a wound healing rate of 98%, with most wounds exhibiting new skin coverage. The experimental group’s antibacterial efficacy significantly surpassed that of the control group, indicating that under NIR irradiation, the MXenes@PVA hydrogel effectively combated S. aureus-induced bacterial infections. Displaying attributes, such as high toughness, anisotropy, and antimicrobial properties, the MXenes@PVA hydrogel demonstrates potential as a compelling dressing for antibacterial wound healing (Li et al., 2022). Yang et al. (2022) devised an antibacterial fibrous membrane using electrospun poly(caprolactone) scaffolds integrated with polydopamine-coated MXene/Ag3PO4 bio-heterojunctions (MX@AgP bio-HJs). In vivo findings revealed that these nanofibrous membranes could transform an infected wound microenvironment into a regenerative one by eradicating bacteria, halting bleeding, enhancing epithelialization, encouraging collagen deposition on the wound bed, and promoting angiogenesis (Yang et al., 2022). Yang et al. (2021) developed and produced a four-channel synergistic antibacterial nano-platform comprising 2D bio-heterojunctions HJs of

320

A. Velidandi et al.

Ti3C2MXene and molybdenum disulfide (MoS2). Through in vivo assessments utilizing a mouse-infected wound model, the nano-platform exhibited remarkable efficacy in disinfecting bacterial infections and expediting the process of wound healing (Yang et al., 2021).

Wearable Antibacterial Fabrics There has been significant public fascination with smart and flexible electronic devices such as wearable sensors, medical monitoring tools, and soft robots (Pei et al., 2021). Textile materials, due to their comfort, skin-friendliness, breathability, and flexibility, have emerged as a favorable choice for creating flexible wearable devices (Hao et al., 2022). However, achieving multifunctional attributes while preserving the intrinsic benefits of textiles remains a considerable challenge. Capitalizing on the unique surface chemical properties of MXenes, including adjustable surface characteristics, tunable bandgap, remarkable mechanical strength, and electrical conductivity comparable to metals, these materials have found wide application in producing flexible smart fabrics using techniques like dip coating and spray coating (Nie et al., 2021; Pei et al., 2021). Yan et  al. (2021) detailed the creation of a silk fabric adorned with MXenes, resulting in a textile that exhibited commendable UV protection, electrothermal conversion capabilities, and photothermal antibacterial properties. This was accomplished through the in situ dip-coating of Ti3C2Tx nanosheets onto the silk fabric. Despite the integration of MXene, the resulting MXene@silk fabric still preserves its original attributes of breathability, softness, and skin-friendly nature. Moreover, the fabric’s UV protection factor, along with its ability to counter E. coli bacteria within just 20 min of contact, achieved levels of over 110% and 99%, respectively. This showcases remarkable UV resistance and swift antibacterial efficacy (Yan et al., 2021). Zhang et al. (2019) reported a remarkably flexible and self-repairing hydrogel electrode, consisting of MXene (Ti3C2Tx) and PVA, which has been developed for use in capacitive strain sensors designed for electronic skin. The addition of MXene to the PVA significantly enhances the hydrogel’s conductivity and its ability to self-­heal. This electrode demonstrates exceptional stretchability, with a breaking point at approximately 1200% and rapid self-healing within about 0.15 s. A capacitive sensor employing these electrodes exhibits exceptional linearity, extending up to 200%, minimal hysteresis, a sensitivity of roughly 0.40, and robust mechanical durability, with only a 5.8% reduction in relative capacitance change after 10,000 cycles. Furthermore, this sensor maintains its performance even after a selfhealing test, underscoring its potential for monitoring human motion (Zhang et al., 2019).

MXene-Based Nanocomposites for Antibacterial Applications

321

 otential Applications of MXene-Based Materials in Fighting P COVID-19 MXene-based materials have shown great potential in the fight against COVID-19 due to their unique properties (Panda et al., 2022). MXenes are highly conductive, have a high surface area, and can be easily functionalized with various molecules, making them ideal candidates for drug delivery systems. Researchers have investigated the use of MXenes for delivering antiviral drugs to infected cells, which could potentially improve treatment efficacy and reduce side effects. Moreover, MXenes can be incorporated into face masks or other personal protective equipment to provide an additional layer of protection against the virus (Dwivedi et al., 2021; Saraf et al., 2021). MXene coatings can inhibit the growth of viruses and bacteria, including coronaviruses, and can be used to develop surface coatings for frequently touched surfaces, such as doorknobs and handrails, to prevent the spread of the virus (Panda et al., 2022). In addition to COVID-19, MXene-based materials have also shown potential for other applications in the medical field, such as cancer therapy and tissue engineering (Mohajer et al., 2022). However, it is important to note that research in this field is still in its early stages, and more studies are needed to fully explore the potential of MXene-based materials for COVID-19 prevention and treatment, as well as other medical applications. Lately, the study by Liu et al. describes the development of a biosensor using MXene nanoprobes for the simultaneous detection of Influenza A virus and SARS-­ CoV-­2 (Liu et al., 2023c). The assay is based on immunochromatography, where the presence of a target virus is detected by binding specific antibodies to the virus. The use of MXene-based materials and quantum dots as fluorescent labels enhances the sensitivity and specificity of the assay, allowing for the detection of the viruses at very low concentrations. The study explains that the biosensor can detect 1 ng/mL of 2.4 pg/mL FluA and 1 ng/mL or 6.2 pg/mL SARS-COV-2 by its colorimetric/ fluorescence signals, respectively, within 20 min. This means that the assay is highly sensitive and can detect very low concentrations of the viruses in a short amount of time. This is a significant improvement over other diagnostic methods that may require longer processing times or higher concentrations of the virus to be detected. One of the major advantages of this assay is its ability to detect multiple targets simultaneously, which could lead to improved diagnostic accuracy and reduced need for multiple tests. Additionally, the use of MXene-based materials could lead to the development of low-cost, portable diagnostic devices that can be used in resource-limited settings. Overall, this development could have significant implications for the diagnosis and management of COVID-19 and influenza A virus infections, as it offers a highly sensitive and specific method for detecting both viruses simultaneously. Bolourinezhas et al. developed a biosensor that utilizes a MXene/Pt/C (TibC2TX/ carbon platinum) nanocomposite and DNA/RNA hybridization for rapid detection

322

A. Velidandi et al.

of COVID-19 (Bolourinezhad et al., 2023). The biosensor employs electrochemical techniques to identify the presence of COVID-19 in a sample. The MXene/Pt/C nanocomposite serves as the electrode material, while DNA/RNA hybridization is used to capture the viral RNA. The researchers reported that the biosensor demonstrated high sensitivity, detecting as low as 60 copies/mL. This biosensor offers a fast and accurate method for COVID-19 detection, which could aid in controlling the spread of the virus. It can be applied for detecting COVID-19 in nasopharyngeal swabs, serum, and saliva samples. Researchers have utilized Ta2C-MXene to sensitize a device that detects ultrafine plasmon spectroscopy combs, enabling the detection of small amounts of nucleic acids (0.2  pg/mL) (Yang et  al., 2023). This could aid in diagnosing pathogenic infections caused by microorganisms such as bacteria and viruses. Additionally, another researcher has developed a sensor from MXene made of transition metal carbides and nitrides. They combined MXene with aptamers, short DNA strands that can bind to specific molecules. The resulting sensor demonstrated high sensitivity and specificity in detecting the SARS-CoV-2 spike protein (at 38.9 fg/mL), accurately distinguishing the virus from other similar molecules (Luo et al., 2023). The sensor could also detect the virus in less than 30 min, making it a promising tool for rapid and accurate diagnosis of COVID-19. Song et  al. describe a method that uses an upconversion luminescence nanoprobe/MXene biosensing platform for COVID-19 point-of-care diagnostics (Song et al., 2022). This method involves using a Nb2CTx (MXene) nanosheet to sensitize a device that can detect upconversion luminescence, which is a type of light emission that occurs when certain materials are excited via light of a different wavelength. By detecting upconversion luminescence, the device can detect the presence of SARS-CoV-2 in a sample, which can help diagnose COVID-19. This method is intended for use in point-of-care settings, meaning it can be used outside of a laboratory. By using this method, healthcare providers can quickly and accurately detect the presence of SARS-CoV-2 in patients, aiding in the diagnosis and management of COVID-19. Wu et al. describe a different method for detecting SARS-CoV-2, which uses a highly sensitive and selective surface plasmon resonance biosensor for the detection of SARS-CoV-2 spike S1 protein (Wu et al., 2022). This method involves using a MXene (Ti3C2) biosensor that can detect changes in the refractive index of a sample when SARS-CoV-2 spike S1 protein is present. The biosensor is highly sensitive and selective, meaning it can detect very small amounts of the virus and distinguish it from other molecules in the sample. This method is also intended for use in laboratories. However, these methods use different materials and technologies to detect SARS-CoV-2, but they both aim to achieve highly sensitive and selective detection of the virus (Mi et al., 2021; Peng et al., 2021). The Song et al. 2022 method is intended for use in point-of-care settings, while the Wu et  al. 2022 method is intended for laboratory use. These methods contribute to the development of sensitive and selective tools for diagnosing COVID-19 in different settings.

MXene-Based Nanocomposites for Antibacterial Applications

323

Limitations and Future Research Perspectives Despite thorough investigation and notable achievements up to this point, several fundamental matters still lack resolution. 1. The utilization of etchants containing fluorine, a common practice in the prevalent preparation process, presents notable environmental and health hazards for researchers. It is imperative to develop more sophisticated MXene preparation techniques to facilitate practical applications. In experimental terms, there is a demand to investigate novel etchants and intercalants for a viable MXene synthesis protocol, aiming to achieve desired surface termination groups and finely adjustable properties for MXenes (Hao et al., 2022). 2. Biocompatibility holds a critical significance within the realm of therapeutic interventions. However, our comprehension of the prolonged impacts on human health and the mechanisms underlying cytotoxicity remains inadequate. While considerable progress has been achieved in in  vivo treatments and short-term safety has been validated in these investigations, it is imperative to conduct further research and assessments to scrutinize their enduring biosafety. Additionally, the potential consequences of degradation products must be duly acknowledged, as they might result in bioaccumulation and tissue toxicity (Hao et al., 2022). 3. MXenes can undergo easy decomposition, leading to oxide formation, influenced by the collaborative effects of air, moisture, and light. In real-world applications, ensuring the stability of MXenes are paramount to maintain their antibacterial efficacy. Consequently, investigating and comprehending the oxidation kinetics of MXenes holds immense importance, enabling the prediction of alterations in composition and performance over extended periods (Hao et al., 2022).

Conclusion Nanotechnology has emerged as a promising technological frontier with significant potential across various healthcare domains, presenting a durable and efficient strategy for addressing the AMR threat. MXene, being a class of two-dimensional nanomaterials characterized by its substantial specific surface area, distinct photodynamic attributes, and abundant functional groups, has garnered significant interest for its potential in the realm of antibacterial and biomedical applications. Overcoming the shortcomings in the application of MXenes in real-time scenario will be a boon to humankind. Acknowledgments  The authors thank the Department of Biotechnology and Department of Physics, National Institute of Technology, Warangal, Telangana, India, for their valuable support.

324

A. Velidandi et al.

References Ahamed, M., Akhtar, M. J., Khan, M. A. M., & Karuppiah, P. (2022). Antibacterial, antifungal, and anticancer potential of two-dimensional Ti3C2Tx MXene. Materials Letters, 327, 133020. https://doi.org/10.1016/j.matlet.2022.133020 Alhabeb, M., Maleski, K., Mathis, T.  S., Sarycheva, A., Hatter, C.  B., Uzun, S., Levitt, A., & Gogotsi, Y. (2018). Selective etching of silicon from Ti 3 SiC 2 (MAX) to obtain 2D titanium carbide (MXene). Angewandte Chemie International Edition, 57(19), 5444–5448. https://doi. org/10.1002/anie.201802232 Alsafari, I. A., Munir, S., Zulfiqar, S., Saif, M. S., Warsi, M. F., & Shahid, M. (2021). Synthesis, characterization, photocatalytic and antibacterial properties of copper ferrite/MXene (CuFe2O4/ Ti3C2) nanohybrids. Ceramics International, 47(20), 28874–28883. https://doi.org/10.1016/j. ceramint.2021.07.048 Anasori, B., Xie, Y., Beidaghi, M., Lu, J., Hosler, B.  C., Hultman, L., Kent, P.  R. C., Gogotsi, Y., & Barsoum, M. W. (2015). Two-dimensional, ordered, double transition metals carbides (MXenes). ACS Nano, 9(10), 9507–9516. https://doi.org/10.1021/acsnano.5b03591 Bolourinezhad, M., Rezayi, M., Meshkat, Z., Soleimanpour, S., Mojarrad, M., Zibadi, F., Aghaee-­ Bakhtiari, S. H., & Taghdisi, S. M. (2023). Design of a rapid electrochemical biosensor based on MXene/Pt/C nanocomposite and DNA/RNA hybridization for the detection of COVID-19. Talanta, 265, 124804. https://doi.org/10.1016/j.talanta.2023.124804 Reygaert, W. C. (2018). An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiology, 4(3), 482–501. https://doi.org/10.3934/microbiol.2018.3.482 Chen, X., Wang, J., Endo, Y., Liu, G., Wang, N., & Shao, Z. (2023). Natural photothermal-­ responsive MXene-based antimicrobial nanomaterials Ti3C2/Au NPs for the treatment of deep Staphylococcus aureus-infected wound. Materials & Design, 232, 112138. https://doi. org/10.1016/j.matdes.2023.112138 Dash, S. R., & Kundu, C. N. (2023). Advances in nanomedicine for the treatment of infectious diseases caused by viruses. Biomaterials Science, 11(10), 3431–3449. https://doi.org/10.1039/ D2BM02066A Dong, Y., Liu, J., Chen, Y., Zhu, T., Li, Y., Zhang, C., Zeng, X., Chen, Q., & Peng, Q. (2023). Photothermal and natural activity-based synergistic antibacterial effects of Ti3C2Tx MXene-­ loaded chitosan hydrogel against methicillin-resistant Staphylococcus aureus. International Journal of Biological Macromolecules, 240, 124482. https://doi.org/10.1016/j. ijbiomac.2023.124482 Dwivedi, N., Dhand, C., Kumar, P., & Srivastava, A.  K. (2021). Emergent 2D materials for combating infectious diseases: The potential of MXenes and MXene–graphene composites to fight against pandemics. Materials Advances, 2(9), 2892–2905. https://doi.org/10.1039/ D1MA00003A Fu, Y., Cheng, Y., Wei, Q., Zhao, Y., Zhang, W., Yang, Y., & Li, D. (2022). Multifunctional biomass composite aerogel co-modified by MXene and Ag nanowires for health monitoring and synergistic antibacterial applications. Applied Surface Science, 598, 153783. https://doi. org/10.1016/j.apsusc.2022.153783 Fu, Y., Li, C., Cheng, Y., He, Y., Zhang, W., Wei, Q., & Li, D. (2023). Biomass aerogel composite containing BaTiO3 nanoparticles and MXene for highly sensitive self-powered sensor and photothermal antibacterial applications. Composites Part A: Applied Science and Manufacturing, 173, 107663. https://doi.org/10.1016/j.compositesa.2023.107663 Gao, Y., Dong, Y., Yang, S., Mo, A., Zeng, X., Chen, Q., & Peng, Q. (2022). Size-dependent photothermal antibacterial activity of Ti C T MXene nanosheets against methicillin-resistant Staphylococcus aureus. Journal of Colloid and Interface Science, 617, 533–541. https://doi. org/10.1016/j.jcis.2022.03.032 George, S. M., & Kandasubramanian, B. (2020). Advancements in MXene-polymer composites for various biomedical applications. Ceramics International, 46(7), 8522–8535. https://doi. org/10.1016/j.ceramint.2019.12.257

MXene-Based Nanocomposites for Antibacterial Applications

325

Ghazaly, A. El, Ahmed, H., Rezk, A. R., Halim, J., Persson, P. O. Å., Yeo, L. Y., & Rosen, J. (2021). Ultrafast, one-step, salt-solution-based acoustic synthesis of Ti3 C2 MXene. ACS Nano, 15(3), 4287–4293. https://doi.org/10.1021/acsnano.0c07242 Hao, S., Han, H., Yang, Z., Chen, M., Jiang, Y., Lu, G., Dong, L., Wen, H., Li, H., Liu, J., Wu, L., Wang, Z., & Wang, F. (2022). Recent advancements on photothermal conversion and antibacterial applications over MXenes-based materials. Nano-Micro Letters, 14(1), 178. https://doi. org/10.1007/s40820-­022-­00901-­w He, J., Shi, M., Liang, Y., & Guo, B. (2020). Conductive adhesive self-healing nanocomposite hydrogel wound dressing for photothermal therapy of infected full-thickness skin wounds. Chemical Engineering Journal, 394, 124888. https://doi.org/10.1016/j.cej.2020.124888 He, Q., Hu, H., Han, J., & Zhao, Z. (2022). Double transition-metal TiVCTX MXene with dual-­ functional antibacterial capability. Materials Letters, 308, 131100. https://doi.org/10.1016/j. matlet.2021.131100 He, X., Koo, S., Obeng, E., Sharma, A., Shen, J., & Kim, J. S. (2023). Emerging 2D MXenes for antibacterial applications: Current status, challenges, and prospects. Coordination Chemistry Reviews, 492, 215275. https://doi.org/10.1016/j.ccr.2023.215275 Hu, Y., Xu, Z., Pu, J., Hu, L., Zi, Y., Wang, M., Feng, X., & Huang, W. (2022). 2D MXene Ti3C2Tx nanosheets in the development of a mechanically enhanced and efficient antibacterial dental resin composite. Frontiers in Chemistry, 10, 1090905. https://doi.org/10.3389/ fchem.2022.1090905 Hua, S., Huang, B., Le, Z., & Huang, Q. (2023). Mo-based Mo2Ti2C3 MXene as photothermal nanoagents to eradicating methicillin-resistant Staphylococcus aureus with photothermal therapy. Materials & Design, 231, 112033. https://doi.org/10.1016/j.matdes.2023.112033 Husmann, S., Budak, Ö., Shim, H., Liang, K., Aslan, M., Kruth, A., Quade, A., Naguib, M., & Presser, V. (2020). Ionic liquid-based synthesis of MXene. Chemical Communications, 56(75), 11082–11085. https://doi.org/10.1039/D0CC03189E Idumah, C. I., Obele, C. M., & Enwerem, U. E. (2021). On interfacial and surface behavior of polymeric MXenes nanoarchitectures and applications. Current Research in Green and Sustainable Chemistry, 4, 100104. https://doi.org/10.1016/j.crgsc.2021.100104 Jatoi, A. S., Mubarak, N. M., Hashmi, Z., Solangi, N. H., Karri, R. R., Tan, Y. H., Mazari, S. A., Koduru, J.  R., & Alfantazi, A. (2023). New insights into MXene applications for sustainable environmental remediation. Chemosphere, 313, 137497. https://doi.org/10.1016/j. chemosphere.2022.137497 Jung, S., Zafar, U., Achary, L. S. K., & Koo, C. M. (2023). Ligand chemistry for surface functionalization in MXenes: A review. EcoMat, e12395. https://doi.org/10.1002/ eom2.12395 Kajiyama, S., Szabova, L., Iinuma, H., Sugahara, A., Gotoh, K., Sodeyama, K., Tateyama, Y., Okubo, M., & Yamada, A. (2017). Enhanced Li-ion accessibility in MXene titanium carbide by steric chloride termination. Advanced Energy Materials, 7(9), 1601873. https://doi. org/10.1002/aenm.201601873 Khatoon, U.  T., Velidandi, A., & Nageswara Rao, G.  V. S. (2023). Sodium borohydride mediated synthesis of nano-sized silver particles: Their characterization, anti-microbial and cytotoxicity studies. Materials Chemistry and Physics, 294, 126997. https://doi.org/10.1016/j. matchemphys.2022.126997 Klein, E. Y., Van Boeckel, T. P., Martinez, E. M., Pant, S., Gandra, S., Levin, S. A., Goossens, H., & Laxminarayan, R. (2018). Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proceedings of the National Academy of Sciences, 115(15), E3463–E3470. https://doi.org/10.1073/pnas.1717295115 Koyappayil, A., Chavan, S. G., Roh, Y.-G., & Lee, M.-H. (2022). Advances of MXenes; perspectives on biomedical research. Biosensors, 12(7), 454. https://doi.org/10.3390/bios12070454 Li, H., Fan, R., Zou, B., Yan, J., Shi, Q., & Guo, G. (2023). Roles of MXenes in biomedical applications: Recent developments and prospects. Journal of Nanobiotechnology, 21(1), 73. https:// doi.org/10.1186/s12951-­023-­01809-­2

326

A. Velidandi et al.

Li, M., Lu, J., Luo, K., Li, Y., Chang, K., Chen, K., Zhou, J., Rosen, J., Hultman, L., Eklund, P., Persson, P. O. Å., Du, S., Chai, Z., Huang, Z., & Huang, Q. (2019). Element replacement approach by reaction with Lewis acidic molten salts to synthesize Nanolaminated MAX phases and MXenes. Journal of the American Chemical Society, 141(11), 4730–4737. https://doi. org/10.1021/jacs.9b00574 Li, Q., Wang, W., Feng, H., Cao, L., Wang, H., Wang, D., & Chen, S. (2021). NIR-triggered photocatalytic and photothermal performance for sterilization based on copper sulfide nanoparticles anchored on Ti3C2T MXene. Journal of Colloid and Interface Science, 604, 810–822. https:// doi.org/10.1016/j.jcis.2021.07.048 Li, T., Yao, L., Liu, Q., Gu, J., Luo, R., Li, J., Yan, X., Wang, W., Liu, P., Chen, B., Zhang, W., Abbas, W., Naz, R., & Zhang, D. (2018). Fluorine-free synthesis of high-purity Ti 3 C 2 T x (T=OH, O) via alkali treatment. Angewandte Chemie International Edition, 57(21), 6115–6119. https://doi.org/10.1002/anie.201800887 Li, Y., Han, M., Cai, Y., Jiang, B., Zhang, Y., Yuan, B., Zhou, F., & Cao, C. (2022). Muscle-inspired MXene/PVA hydrogel with high toughness and photothermal therapy for promoting bacteria-­ infected wound healing. Biomaterials Science, 10(4), 1068–1082. https://doi.org/10.1039/ D1BM01604K Li, Y., Shao, H., Lin, Z., Lu, J., Liu, L., Duployer, B., Persson, P. O. Å., Eklund, P., Hultman, L., Li, M., Chen, K., Zha, X.-H., Du, S., Rozier, P., Chai, Z., Raymundo-Piñero, E., Taberna, P.-L., Simon, P., & Huang, Q. (2020). A general Lewis acidic etching route for preparing MXenes with enhanced electrochemical performance in non-aqueous electrolyte. Nature Materials, 19(8), 894–899. https://doi.org/10.1038/s41563-­020-­0657-­0 Liu, L., Zhu, M., Ma, Z., Xu, X., Mohesen Seraji, S., Yu, B., Sun, Z., Wang, H., & Song, P. (2022). A reactive copper-organophosphate-MXene heterostructure enabled antibacterial, self-­extinguishing and mechanically robust polymer nanocomposites. Chemical Engineering Journal, 430, 132712. https://doi.org/10.1016/j.cej.2021.132712 Liu, W., Kang, S., Zhang, Q., Chen, S., Yang, Q., & Yan, B. (2023a). Self-assembly fabrication of chitosan-tannic acid/MXene composite film with excellent antibacterial and antioxidant properties for fruit preservation. Food Chemistry, 410, 135405. https://doi.org/10.1016/j. foodchem.2023.135405 Liu, Y., He, X., Feng, J., Wang, D., Obeng, E., Yu, C., Song, Y., Shen, J., & Li, Z.  P. (2023b). Engineering a new member of MXenes M5C4 phases nanoplatforms as synergistically photothermal and chemodynamic therapeutics for methicillin-resistant Staphylococcus aureus. Chemical Engineering Journal, 466, 143004. https://doi.org/10.1016/J.CEJ.2023.143004 Liu, Y., Lv, Y., Chen, W., Yang, X., Cheng, X., Rong, Z., & Wang, S. (2023c). Development of a fluorescent Immunochromatographic assay based on quantum dot-functionalized two-­ dimensional monolayer Ti 3 C 2 MXene Nanoprobes for the simultaneous detection of influenza A virus and SARS-CoV-2. ACS Applied Materials & Interfaces, 15(30), 35872–35883. https:// doi.org/10.1021/acsami.3c05424 Luo, Y., Jiang, X., Zhang, R., Shen, C., Li, M., Zhao, Z., Lv, M., Sun, S., Sun, X., & Ying, B. (2023). MXene-based aptameric fluorosensor for sensitive and rapid detection of COVID-19. Small, 19(23), e2301146. https://doi.org/10.1002/smll.202301146 Manawi, Y., Ihsanullah, S., & A., Al-Ansari, T., & Atieh, M. (2018). A review of carbon nanomaterials’ synthesis via the chemical vapor deposition (CVD) method. Materials, 11(5), 822. https://doi.org/10.3390/ma11050822 Mansoorianfar, M., Shahin, K., Hojjati-Najafabadi, A., & Pei, R. (2022). MXene–laden bacteriophage: A new antibacterial candidate to control bacterial contamination in water. Chemosphere, 290, 133383. https://doi.org/10.1016/j.chemosphere.2021.133383 Mayerberger, E. A., Street, R. M., McDaniel, R. M., Barsoum, M. W., & Schauer, C. L. (2018). Antibacterial properties of electrospun Ti3 C2 Tz (MXene)/chitosan nanofibers. RSC Advances, 8(62), 35386–35394. https://doi.org/10.1039/C8RA06274A Mehrabi, M. R., Soltani, M., Chiani, M., Raahemifar, K., & Farhangi, A. (2023). Nanomedicine: New Frontiers in fighting microbial infections. Nanomaterials, 13(3), 483. https://doi. org/10.3390/nano13030483

MXene-Based Nanocomposites for Antibacterial Applications

327

Mei, J., Ayoko, G.  A., Hu, C., Bell, J.  M., & Sun, Z. (2020a). Two-dimensional fluorine-free mesoporous Mo2C MXene via UV-induced selective etching of Mo2Ga2C for energy storage. Sustainable Materials and Technologies, 25, e00156. https://doi.org/10.1016/j.susmat.2020.e00156 Mei, J., Ayoko, G. A., Hu, C., & Sun, Z. (2020b). Thermal reduction of sulfur-containing MAX phase for MXene production. Chemical Engineering Journal, 395, 125111. https://doi. org/10.1016/j.cej.2020.125111 Mi, X., Li, H., Tan, R., Feng, B., & Tu, Y. (2021). The TDs/aptamer cTnI biosensors based on HCR and Au/Ti3C2-MXene amplification for screening serious patient in COVID-19 pandemic. Biosensors and Bioelectronics, 192, 113482. https://doi.org/10.1016/j.bios.2021.113482 Mohajer, F., Ziarani, G.  M., Badiei, A., Iravani, S., & Varma, R.  S. (2022). Advanced MXene-­ based micro- and Nanosystems for targeted drug delivery in cancer therapy. Micromachines, 13(10), 1773. https://doi.org/10.3390/mi13101773 Murray, C. J. L., Ikuta, K. S., Sharara, F., Swetschinski, L., Robles Aguilar, G., Gray, A., Han, C., Bisignano, C., Rao, P., Wool, E., Johnson, S. C., Browne, A. J., Chipeta, M. G., Fell, F., Hackett, S., Haines-Woodhouse, G., Kashef Hamadani, B. H., Kumaran, E. A. P., McManigal, B., et  al. (2022). Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. The Lancet, 399(10325), 629–655. https://doi.org/10.1016/S0140-­6736(21)02724-­0 Naguib, M., Kurtoglu, M., Presser, V., Lu, J., Niu, J., Heon, M., Hultman, L., Gogotsi, Y., & Barsoum, M. W. (2011). Two-dimensional nanocrystals produced by exfoliation of Ti3AlC2. Advanced Materials, 23(37), 4248–4253. https://doi.org/10.1002/adma.201102306 Nie, X., Wu, S., Huang, F., Wang, Q., & Wei, Q. (2021). Smart textiles with self-disinfection and photothermochromic effects. ACS Applied Materials and Interfaces, 13(2), 2245–2255. https:// doi.org/10.1021/acsami.0c18474 Panda, S., Deshmukh, K., Mustansar Hussain, C., & Khadheer Pasha, S. K. (2022). 2D MXenes for combatting COVID-19 pandemic: A perspective on latest developments and innovations. FlatChem, 33, 100377. https://doi.org/10.1016/j.flatc.2022.100377 Pang, S. Y., Wong, Y. T., Yuan, S., Liu, Y., Tsang, M. K., Yang, Z., Huang, H., Wong, W. T., & Hao, J. (2019). Universal strategy for HF-free facile and rapid synthesis of two-dimensional MXenes as multifunctional energy materials. Journal of the American Chemical Society, 141(24), 9610–9616. https://doi.org/10.1021/jacs.9b02578 Patel, J., Harant, A., Fernandes, G., Mwamelo, A. J., Hein, W., Dekker, D., & Sridhar, D. (2023). Measuring the global response to antimicrobial resistance, 2020–21: A systematic governance analysis of 114 countries. The Lancet Infectious Diseases, 23(6), 706–718. https://doi. org/10.1016/S1473-­3099(22)00796-­4 Pei, Y., Zhang, X., Hui, Z., Zhou, J., Huang, X., Sun, G., & Huang, W. (2021). Ti3C2TXMXene for sensing applications: Recent progress, design principles, and future perspectives. ACS Nano, 15(3), 3996–4017. https://doi.org/10.1021/acsnano.1c00248 Peng, Y., Lin, C., Long, L., Masaki, T., Tang, M., Yang, L., Liu, J., Huang, Z., Li, Z., Luo, X., Lombardi, J. R., & Yang, Y. (2021). Charge-transfer resonance and electromagnetic enhancement synergistically enabling MXenes with excellent SERS sensitivity for SARS-CoV-2 S protein detection. Nano-Micro Letters, 13(1), 52. https://doi.org/10.1007/s40820-­020-­00565-­4 PRESS RELEASE: High-level meeting on antimicrobial resistance | General Assembly of the United Nations. (2023). Retrieved September 1, 2023, from https://www.un.org/pga/71/2016/09/21/ press-­release-­hl-­meeting-­on-­antimicrobial-­resistance/ Qian, G., Zhang, L., Shuai, Y., Wu, X., Zeng, Z., Peng, S., & Shuai, C. (2023). 3D-printed CuFe2O4-MXene/PLLA antibacterial tracheal scaffold against implantation-associated infection. Applied Surface Science, 614, 156108. https://doi.org/10.1016/j.apsusc.2022.156108 Rajwar, T.  K., Pradhan, D., Halder, J., Rai, V.  K., Kar, B., Ghosh, G., & Rath, G. (2023). Opportunity in nanomedicine to counter the challenges of current drug delivery approaches used for the treatment of malaria: A review. Journal of Drug Targeting, 31(4), 354–368. https:// doi.org/10.1080/1061186X.2022.2164290

328

A. Velidandi et al.

Rasheed, T., Rasheed, A., Munir, S., Ajmal, S., Muhammad Shahzad, Z., Alsafari, I. A., Ragab, S. A., Agboola, P. O., & Shakir, I. (2021). A cost-effective approach to synthesize NiFe2O4/ MXene heterostructures for enhanced photodegradation performance and anti-bacterial activity. Advanced Powder Technology, 32(7), 2248–2257. https://doi.org/10.1016/j.apt.2021.05.006 Rasool, K., Helal, M., Ali, A., Ren, C. E., Gogotsi, Y., & Mahmoud, K. A. (2016). Antibacterial activity of Ti3 C2 Tx MXene. ACS Nano, 10(3), 3674–3684. https://doi.org/10.1021/ acsnano.6b00181 Rasool, K., Mahmoud, K. A., Johnson, D. J., Helal, M., Berdiyorov, G. R., & Gogotsi, Y. (2017). Efficient antibacterial membrane based on two-dimensional Ti3C2Tx (MXene) Nanosheets. Scientific Reports, 7(1), 1598. https://doi.org/10.1038/s41598-­017-­01714-­3 Rosenkranz, A., Perini, G., Aguilar-Hurtado, J.  Y., Zambrano, D.  F., Wang, B., Niccolini, B., Henriques, P.  C., Rosa, E., De Maio, F., Delogu, G., De Spirito, M., Palmieri, V., & Papi, M. (2021). Laser-mediated antibacterial effects of few- and multi-layer Ti3C2Tx MXenes. Applied Surface Science, 567, 150795. https://doi.org/10.1016/j.apsusc.2021.150795 Sana, S.  S., Santhamoorthy, M., Haldar, R., Raorane, C.  J., Iravani, S., Varma, R.  S., & Kim, S.-C. (2023). Recent advances on MXene-based hydrogels for antibacterial and drug delivery applications. Process Biochemistry, 132, 200–220. https://doi.org/10.1016/j. procbio.2023.06.022 Saraf, M., Tavakkoli Yaraki, M., Prateek, T., & Y. N., & Gupta, R. K. (2021). Insights and perspectives regarding nanostructured fluorescent materials toward tackling COVID-19 and future pandemics. ACS Applied Nano Materials, 4(2), 911–948. https://doi.org/10.1021/acsanm.0c02945 Seidi, F., Arabi Shamsabadi, A., Dadashi Firouzjaei, M., Elliott, M., Saeb, M. R., Huang, Y., Li, C., Xiao, H., & Anasori, B. (2023). MXenes antibacterial properties and applications: A review and perspective. Small, 19(14), e2206716. https://doi.org/10.1002/smll.202206716 Shi, H., Zhang, P., Liu, Z., Park, S., Lohe, M.  R., Wu, Y., Shaygan Nia, A., Yang, S., & Feng, X. (2021). Ambient-stable two-dimensional titanium carbide (MXene) enabled by iodine etching. Angewandte Chemie International Edition, 60(16), 8689–8693. https://doi.org/10.1002/ anie.202015627 Solangi, N. H., Mazari, S. A., Mubarak, N. M., Karri, R. R., Rajamohan, N., & Vo, D.-V. N. (2023). Recent trends in MXene-based material for biomedical applications. Environmental Research, 222, 115337. https://doi.org/10.1016/j.envres.2023.115337 Song, M., Ma, Y., Li, L., Wong, M.-C., Wang, P., Chen, J., Chen, H., Wang, F., & Hao, J. (2022). Multiplexed detection of SARS-CoV-2 based on upconversion luminescence nanoprobe/ MXene biosensing platform for COVID-19 point-of-care diagnostics. Materials & Design, 223, 111249. https://doi.org/10.1016/j.matdes.2022.111249 Su, X., Sha, Q., Gao, X., Li, J., Wu, Y., Li, W., Wu, W., Han, N., & Zhang, X. (2023). Lightweight, multifunctional smart MXene@PET non-woven with electric/photothermal conversion, antibacterial and flame retardant properties. Applied Surface Science, 639, 158205. https://doi. org/10.1016/j.apsusc.2023.158205 Tavakolian, M., Jafari, S. M., & van de Ven, T. G. M. (2020). A review on surface-functionalized cellulosic nanostructures as biocompatible antibacterial materials. Nano-Micro Letters, 12(73). https://doi.org/10.1007/s40820-­020-­0408-­4 Urbankowski, P., Anasori, B., Hantanasirisakul, K., Yang, L., Zhang, L., Haines, B., May, S. J., Billinge, S. J. L., & Gogotsi, Y. (2017). 2D molybdenum and vanadium nitrides synthesized by ammoniation of 2D transition metal carbides (MXenes). Nanoscale, 9(45), 17722–17730. https://doi.org/10.1039/C7NR06721F Vankdoth, S., Velidandi, A., Sarvepalli, M., & Vangalapati, M. (2022). Role of plant (tulasi, neem and turmeric) extracts in defining the morphological, toxicity and catalytic properties of silver nanoparticles. Inorganic Chemistry Communications, 140(February), 109476. https://doi. org/10.1016/j.inoche.2022.109476 Vasyukova, I. A., Zakharova, O. V., Kuznetsov, D. V., & Gusev, A. A. (2022). Synthesis, toxicity assessment, environmental and biomedical applications of MXenes: A review. Nanomaterials, 12(11), 1797. https://doi.org/10.3390/nano12111797

MXene-Based Nanocomposites for Antibacterial Applications

329

Velidandi, A., Dahariya, S., Pabbathi, N. P. P., Kalivarathan, D., & Baadhe, R. R. (2020). A review on synthesis, applications, toxicity, risk assessment and limitations of plant extracts synthesized silver nanoparticles. Nano World Journal, 6(3), 35–60. https://doi.org/10.17756/nwj.2020-­079 Velidandi, A., Sarvepalli, M., Aramanda, P., Amudala, M.  L., & Baadhe, R.  R. (2023). Effect of size on physicochemical, antibacterial, and catalytic properties of Neolamarckia cadamba (burflower-tree) synthesized silver/silver chloride nanoparticles. Environmental Science and Pollution Research, 0123456789, 63231. https://doi.org/10.1007/s11356-­023-­26427-­1 Venkateshalu, S., & Grace, A. N. (2020). MXenes—A new class of 2D layered materials: Synthesis, properties, applications as supercapacitor electrode and beyond. Applied Materials Today, 18, 100509. https://doi.org/10.1016/j.apmt.2019.100509 Walsh, T.  R., Gales, A.  C., Laxminarayan, R., & Dodd, P.  C. (2023). Antimicrobial resistance: Addressing a global threat to humanity. PLoS Medicine, 20(7), e1004264. https://doi. org/10.1371/journal.pmed.1004264 Wang, Q., Zang, C., Chan, Y. K., Wang, S., Yang, W., Deng, Y., Zhu, T., & He, M. (2023). CoFe2O4/ MXene nanosheets modified hydrogel on PEEK with phototherapeutic and GPx-mimetic activities for anti-pathogens in infectious bone defect repairment. Materials Chemistry and Physics, 308, 128269. https://doi.org/10.1016/j.matchemphys.2023.128269 Wang, W., Feng, H., Liu, J., Zhang, M., Liu, S., Feng, C., & Chen, S. (2020). A photo catalyst of cuprous oxide anchored MXene nanosheet for dramatic enhancement of synergistic antibacterial ability. Chemical Engineering Journal, 386, 124116. https://doi.org/10.1016/j. cej.2020.124116 Warsi, A.-Z., Aziz, F., Zulfiqar, S., Haider, S., Shakir, I., & Agboola, P.  O. (2022). Synthesis, characterization, photocatalysis, and antibacterial study of WO3, MXene and WO3/MXene nanocomposite. Nanomaterials, 12(4), 713. https://doi.org/10.3390/nano12040713 Wei, Y., Zhang, P., Soomro, R. A., Zhu, Q., & Xu, B. (2021). Advances in the synthesis of 2D MXenes. Advanced Materials, 33(39), 2103148. https://doi.org/10.1002/adma.202103148 WHO. (2021). 10 global health issues to track in 2021. Retrieved September 1, 2023, from https:// www.who.int/news-­room/spotlight/10-­global-­health-­issues-­to-­track-­in-­2021 Wojciechowska, A., Jakubczak, M., Moszczyńska, D., Wójcik, A., Prenger, K., Naguib, M., & Jastrzębska, A.  M. (2023). Engineering the surface of Nbn+1CnT MXenes to versatile bio-activity towards microorganisms. Biomaterials Advances, 153, 213581. https://doi. org/10.1016/j.bioadv.2023.213581 Wu, F., Zheng, H., Wang, W., Wu, Q., Zhang, Q., Guo, J., Pu, B., Shi, X., Li, J., Chen, X., & Hong, W. (2021). Rapid eradication of antibiotic-resistant bacteria and biofilms by MXene and near-­ infrared light through photothermal ablation. Science China Materials, 64(3), 748–758. https:// doi.org/10.1007/s40843-­020-­1451-­7 Wu, P., Qin, Z., Dassanayake, R., Sun, Z., Cao, M., Fu, K., Zhou, Y., & Liu, Y. (2023). Antimicrobial MXene-based conductive alginate hydrogels as flexible electronics. Chemical Engineering Journal, 455, 140546. https://doi.org/10.1016/j.cej.2022.140546 Wu, Q., Wu, W., Chen, F., & Ren, P. (2022). Highly sensitive and selective surface plasmon resonance biosensor for the detection of SARS-CoV-2 spike S1 protein. The Analyst, 147(12), 2809–2818. https://doi.org/10.1039/D2AN00426G Xie, X., Xue, Y., Li, L., Chen, S., Nie, Y., Ding, W., & Wei, Z. (2014). Surface Al leached Ti3AlC2 as a substitute for carbon for use as a catalyst support in a harsh corrosive electrochemical system. Nanoscale, 6(19), 11035–11040. https://doi.org/10.1039/C4NR02080D Xing, C., Chen, S., Liang, X., Liu, Q., Qu, M., Zou, Q., Li, J., Tan, H., Liu, L., Fan, D., & Zhang, H. (2018). Two-dimensional MXene (Ti3C2)-integrated cellulose hydrogels: Toward smart three-dimensional network nanoplatforms exhibiting light-induced swelling and bimodal photothermal/chemotherapy anticancer activity. ACS Applied Materials and Interfaces, 10(33), 27631–27643. https://doi.org/10.1021/acsami.8b08314 Yan, B., Zhou, M., Liao, X., Wang, P., Yu, Y., Yuan, J., & Wang, Q. (2021). Developing a multifunctional silk fabric with dual-driven heating and rapid photothermal antibacterial abilities using high-yield MXene dispersions. ACS Applied Materials and Interfaces, 13(36), 43414–43425. https://doi.org/10.1021/acsami.1c12915

330

A. Velidandi et al.

Yang, J., Naguib, M., Ghidiu, M., Pan, L., Gu, J., Nanda, J., Halim, J., Gogotsi, Y., & Barsoum, M. W. (2016). Two-dimensional Nb-based M 4 C3 solid solutions (MXenes). Journal of the American Ceramic Society, 99(2), 660–666. https://doi.org/10.1111/jace.13922 Yang, S., Zhang, P., Wang, F., Ricciardulli, A. G., Lohe, M. R., Blom, P. W. M., & Feng, X. (2018). Fluoride-free synthesis of two-dimensional titanium carbide (MXene) using A binary aqueous system. Angewandte Chemie International Edition, 57(47), 15491–15495. https://doi. org/10.1002/anie.201809662 Yang, W., Yan, J., Liu, R., Xie, Y., Wang, C., Kou, Z., Li, P., & Jiang, M. (2023). Ultra-sensitive specific detection of nucleic acids in pathogenic infections by Ta2C-MXene sensitization-based ultrafine plasmon spectroscopy combs. Sensors and Actuators B: Chemical, 387, 133785. https://doi.org/10.1016/j.snb.2023.133785 Yang, Y., Zhou, X., Chan, Y. K., Wang, Z., Li, L., Li, J., Liang, K., & Deng, Y. (2022). Photoactivated nanofibrous membrane with self-rechargeable antibacterial function for stubborn infected cutaneous regeneration. Small, 18(12), 2105988. https://doi.org/10.1002/ smll.202105988 Yang, Z., Fu, X., Ma, D., Wang, Y., Peng, L., Shi, J., Sun, J., Gan, X., Deng, Y., & Yang, W. (2021). Growth factor-decorated Ti3 C2 MXene/MoS 2 2D bio-heterojunctions with Quad-Channel photonic disinfection for effective regeneration of bacteria-invaded cutaneous tissue. Small, 17(50), 2103993. https://doi.org/10.1002/smll.202103993 Zada, S., Dai, W., Kai, Z., Lu, H., Meng, X., Zhang, Y., Cheng, Y., Yan, F., Fu, P., Zhang, X., & Dong, H. (2020). Algae extraction controllable delamination of vanadium carbide nanosheets with enhanced near-infrared photothermal performance. Angewandte Chemie International Edition, 59(16), 6601–6606. https://doi.org/10.1002/anie.201916748 Zada, S., Lu, H., Yang, F., Zhang, Y., Cheng, Y., Tang, S., Wei, W., Qiao, Y., Fu, P., Dong, H., & Zhang, X. (2021). V2C Nanosheets as dual-functional antibacterial agents. ACS Applied Bio Materials, 4(5), 4215–4223. https://doi.org/10.1021/acsabm.1c00008 Zhang, J., Wan, L., Gao, Y., Fang, X., Lu, T., Pan, L., & Xuan, F. (2019). Highly stretchable and self-healable MXene/polyvinyl alcohol hydrogel electrode for wearable capacitive electronic skin. Advanced Electronic Materials, 5(7), 1900285. https://doi.org/10.1002/aelm.201900285 Zhang, L., Yin, L., Zhao, R., Di, H., Wang, C., Hui, X., Zhao, D., & Wang, R. (2020). Encapsulating ultrafine Sb nanoparticles in Na+pre-intercalated 3d porous Ti3C2TxMXene nanostructures for enhanced potassium storage performance. ACS Nano, 14(10), 13938–13951. https://doi. org/10.1021/acsnano.0c06360 Zhou, X., Wang, Z., Chan, Y. K., Yang, Y., Jiao, Z., Li, L., Li, J., Liang, K., & Deng, Y. (2022). Infection micromilieu-activated nanocatalytic membrane for orchestrating rapid sterilization and stalled chronic wound regeneration. Advanced Functional Materials, 32(7), 2109469. https://doi.org/10.1002/adfm.202109469 Zhu, X., Zhu, Y., Jia, K., Abraha, B. S., Li, Y., Peng, W., Zhang, F., Fan, X., & Zhang, L. (2020). A near-infrared light-mediated antimicrobial based on Ag/Ti3 C2 Tx for effective synergetic antibacterial applications. Nanoscale, 12(37), 19129–19141. https://doi.org/10.1039/ D0NR04925E Zou, W., McAdorey, A., Yan, H., & Chen, W. (2023). Nanomedicine to overcome antimicrobial resistance: Challenges and prospects. Nanomedicine, 18(5), 471–484. https://doi.org/10.2217/ nnm-­2023-­0022

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological Aspects, Developments, and Challenges Adil M. Allahverdiyev, Sedanur Keleş, Buşra Akgül, Jahid Alakbarli, Malahat Baghırova, and Emrah Ş. Abamor

Overviews Microorganisms are living communities that are too small to be seen with the naked eye and are usually single-celled. Examples of microorganisms are fungi, bacteria, protozoa, and viruses. Pathogenic microorganisms cause disease in humans and animals. Each of these groups is distinct from the others and contributes significantly to a variety of industries, including biotechnology, agriculture, and medicine (Madigan et al., 2019; Wang et al., 2012). Fungi are a group of eukaryotic organisms that include microorganisms such as yeasts and molds. It is a eukaryotic kingdom that can be multicellular or unicellular. Fungi have a cell wall and a nucleus. They feed by absorption in the environment or living organism (Tortora et al., 2016). Bacteria are single-celled prokaryotic microorganisms Bacteria have two cell coverings, the cell membrane on the inside and the cell wall on the top of it. They are classified according to their morphology, gram staining, and oxygen requirements (Castenholz, 2015). Protozoa are single-celled eukaryotic microorganisms. They are larger microorganisms compared to bacteria. Parasites live inside a host A. M. Allahverdiyev (*) · M. Baghırova The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan S. Keleş Department of Metallurgical and Materials Engineering, Karadeniz Technical University, Trabzon, Turkey B. Akgül · E. Ş. Abamor Department of Bioengineering, Yıldız Technical University, Istanbul, Turkey J. Alakbarli The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan Department of Bioengineering, Yıldız Technical University, Istanbul, Turkey © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_15

331

332

A. M. Allahverdiyev et al.

organism and constantly harm it. Some protozoa are parasites and can cause life-­ threatening diseases such as malaria in humans (Wiser, 2022). Viruses are microorganisms that cause infectious diseases in humans, animals, and plants. Viruses are obligate intracellular parasitic microorganisms. They absolutely need the host cell to reproduce. Viruses consist of DNA or RNA genetic material (Delves et al., 2017; Holmes & Rambaut, 2004). In order to prevent and treat diseases caused by microorganisms, it is necessary to understand their properties and functions well (Tortora et al., 2016). Antimicrobial agents have been developed for the treatment of infectious diseases (Huo et  al., 2020). However, the development of antibiotic-resistant strains poses a significant challenge in the treatment of infections (Luksiene, 2005; Miranda et al., 2018). As a result of the development of antibiotic resistance, problems such as prolonged disease duration and increased mortality rates occur. In this context, antibiotic resistance poses a significant threat to health and food safety worldwide (WHO, 2017). Another difficulty in antibiotic therapy is the difficulty encountered in the development of new drugs. Therefore, there has been a decrease in the development of new antibiotics in recent years. These problems have led to efforts to find new treatment methods for the control of microorganisms. To combat resistant microorganisms, the underlying causes of antibiotic resistance should be better understood and new drugs should be developed (Årdal et al., 2019; Boyd et al., 2021; Safarov et al., 2019). The field of nanotechnology, which involves the modification and engineering of materials at the nanoscale level, has provided new opportunities for the development of antimicrobial therapeutics. Recent advancements in nanotechnology have facilitated the development of new materials and techniques for the treatment and detection of infections in this context. These developments include the use of antimicrobial nanoparticles and nanocarriers, which exhibit significant promise in eliminating infections. Nanomaterials can interact with microorganisms in ways that traditional treatments cannot due to their small size, large surface area, and unique characteristics. Overall, recent developments in nanotechnology are raising new expectations for treating microbial diseases and overcoming challenges with drug resistance (Allahverdiyev et al., 2011; dos Santos Ramos et al., 2020; Hetta et al., 2023; Rajabathar et  al., 2020; Ramesh et  al., 2022; Ullah et  al., 2018; Yagublu et al., 2022).

Carbon Nanotube Carbon nanotubes (CNTs) are nanomaterials composed of cylinder-shaped graphene sheets. CNTs can be classified into two distinct categories based on the number of walls present within the tube. These categories include single-walled carbon nanotubes (SWCNT) and multi-walled carbon nanotubes (MWCNT) as shown in Fig. 1. SWCNTs are a single graphene tube, a few nanometers in diameter and usually micrometres in length. By virtue of their distinct composition, they demonstrate particular mechanical, electrical, and thermal characteristics. SWCNTs exhibit

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

333

Fig. 1  Structural composition of SWCNTs and MWCNTs

distinct electrical properties, characterized as either metallic or semiconducting, depending upon their unique chirality. SWCNTs that have metallic properties exhibit higher electrical conductivity. MWCNTs, on the other hand, consist of several graphene tubes nested together, up to 10 times the diameter of SWCNTs. They exhibit similar properties to SWCNTs, but there are some differences in their electronic structure and mechanical properties due to their additional layers. The simplest MWCNTs are double-walled carbon nanotubes (DWCNTs); these types show all the properties of SWCNTs, but are more stable and dense (Arun, 2021; Jackson et  al., 2013; Kharlamova & Kramberger, 2021; Nurazzi et  al., 2021; Shoukat & Khan, 2021; Watt & Gerhardt, 2020). CNTs exhibit sufficient biocompatibility due to their easy interaction with functional groups. In addition to biocompatibility, they are preferred in tissue engineering applications due to their high mechanical strength and antibacterial properties (Kandhola et al., 2023). Furthermore, CNTs support the proliferation and differentiation of various adult stem cells (B. Holmes et al., 2016). However, the hydrophobic nature of CNTs limits their use in certain fields. The addition of functional groups to the sidewalls and open ends of nanotubes primarily enhances their dispersibility and increases their potential for use. The bonding of functional groups can be chemical (covalent) and physical (non-covalent) (Bai et  al., 2011; Prola et al., 2013). CNTs are widely preferred in scientific research for various applications due to their unique physical, chemical, and mechanical properties. They have been extensively investigated, particularly in the biomedical field, for applications such as bio-­ sensing, drug delivery, tissue engineering, biosensors, and imaging (Garg et  al., 2021; Gong et al., 2013; Lekshmi et al., 2020; Prasek et al., 2011; Rahman et al., 2019; Simon et al., 2019; Singh et al., 2022; Xing et al., 2023). CNTs are also utilized in areas, such as electronics, energy storage, water purification, and air filtration (Mondal et al., 2022; Sweetman et al., 2017; Yola & Atar, 2021).

334

A. M. Allahverdiyev et al.

Synthesis of Carbon Nanotubes There are several techniques for the synthesis of CNTs. As a result of years of studies for the synthesis of CNTs, certain methods have emerged. Each of these synthesis methods has been shaped in line with different applications and usage requests. The frequent techniques used for the synthesis of CNTs include chemical vapor deposition (CVD), arc discharge, laser ablation, chemical oxidation, and electrochemical synthesis (Hassan et  al., 2023; Shoukat & Khan, 2021; Szabó et  al., 2010). CVD method is widely preferred in CNT production due to its simplicity and economy. Metal catalysts are also used in this method. The base material coated with the catalyst is placed in the reactor and a carbon source gas is sent into the reactor. Methane, ethylene, or acetylene gases are generally used as carbon source. By increasing the reactor temperature, carbonaceous compounds are decomposed by pyrolysis based reactions and CNTs are formed on the surface of the base material as a result of the interactions between the released atomic carbon and metal catalysts. CVD method is especially chosen for MWCNT production (Herrera-Ramirez et al., 2018; OrtegaZamora et al., 2021; Stout et al., 2013; Wang et al., 2019). The arc discharge method is one of the oldest methods used in CNT synthesis. In the method, an arc is formed between two graphite rods, one anode and one cathode. In order for the process to take place, the arc reactor is filled with inert gas. In this method, transition metals such as iron, nickel, and cobalt are used as catalysts. Catalysts are placed in the centre of the anode particle. As a result of the arc occurring between the graphite rods, some of the carbon evaporated from the anode is recondensed in a cylindrical shape at the cathode. In the arc discharge method, MWCNT is obtained as a result of bombardment with a pure graphite target, while nanotubes obtained from targets containing catalysts are SWCNT in structure. Flow rate, gas pressure and metal concentration are the parameters affecting CNT yield (Baghel et al., 2022; Gacem et al., 2022). Additional methods, including laser ablation, chemical oxidation, and electrochemical synthesis, have been used for CNT production. However, these methods are not as frequently used as CVD and arc discharge methods. Recent advances in the fields of nanoscience and nanotechnology have led to the investigation of methods to synthesize CNTs with appropriate parameters (Prasek et al., 2011; Shiv Charan et al., 2009). Due to the high cost of CNT synthesis, the areas of application are limited, and therefore, new approaches are being explored. To reduce production costs, more economical and readily available materials such as plastics and agricultural waste are being considered as raw material sources for synthesis (Gacem et al., 2022).

Advantages and Disadvantages of CNTs Advantages Mechanical strength: CNTs exhibit mechanical strength and hardness that surpass those of most materials. Therefore, they are preferred for reinforcing metals, ceramics, and polymers. In addition, its high mechanical strength makes it a preferred

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

335

option as a scaffold in tissue engineering applications (Bao et al., 2023; Mostafa et al., 2021). Electrical conductivity: CNTs can conduct electrons over long distances without significant interruption. They therefore have good electrical conductivity, even surpassing copper. Thanks to their electrical conductivity, CNTs are used in electronic applications such as transistors, sensors, and conductive coatings (Rui et al., 2023; Spitalsky et al., 2010). Thermal conductivity: Thanks to their thermal conductivity, CNTs require very low amounts of voltage to reach high temperatures. Therefore, they are preferred in thermal applications as heat sinks and thermal interface materials (Abdulhameed & Halim, 2023; Yadav & Sanserwal, 2022). Biocompatibility: CNTs are biocompatible and do not cause significant cell damage. This property makes them useful in in-body applications. In particular, they are often preferred in biomedical applications such as drug delivery, tissue engineering, and imaging (Saliev, 2019; Singh et al., 2022). Antimicrobial effect: CNTs exhibit an antimicrobial effect by exhibiting various mechanisms against microorganisms. Thanks to these properties, they have become promising candidates for the development of new treatments against viral and bacterial diseases (Deryabin et al., 2010; Kang et al., 2007). Disadvantages Production cost: Large-scale synthesis of CNTs is expensive due to their high purity and the need for specialized equipment and facilities. In addition, their low productivity poses a significant challenge for large-scale synthesis (Gacem et al., 2022). Low dispersibility: CNTs do not disperse well in water, limiting their use in many applications. By adding functional groups to CNTs, their water dispersibility is increased. Therefore, CNTs modified with functional groups are preferred, especially in biomedical applications (Iannazzo et al., 2015; Prola et al., 2013). Toxicity: Some studies have shown that some types of CNTs can be harmful to cells. The type of CNT used and the amount of concentration directly affect the toxicity of cells. Especially CNTs used in high concentrations are suggested to have an oxic effect (Jain et al., 2009).

Toxicity Effect (a Mechanism) on Living Cells CNTs are nanomaterials in which carbon atoms are arranged to form cylindrical structures. Studies on the toxicity potential of CNTs suggest that different factors play a role in their toxicity properties. However, available data suggests that some types of CNTs may be toxic. The physical properties, surface characteristics, and distribution of CNTs have an impact on toxicity (Shvedova et al., 2012). Due to their superior thermal and optical performances, high drug loading rates, and excellent biocompatibility, CNTs have recently attracted interest in biomedical applications. Therefore, the biocompatibility and toxicity effects of CNTs used in

336

A. M. Allahverdiyev et al.

biomedical applications are frequently investigated (Lekshmi et  al., 2020; Singh et al., 2022; Xing et al., 2023). Functionalized MWCNTs are used in many commercial and biomedical applications, but their potential health effects are not well defined. Meindl and colleagues conducted a study to determine whether workers who are continuously exposed to CNTs through the respiratory tract are adversely affected (Meindl et al., 2023). In this study, the dose of MWCNT corresponding to the maximum lifetime exposure of workers was applied to Calu-3 and A549 cells, and its toxicity was analyzed by the MTS assay. No toxic effects were observed as a result of the analysis. In the study by Ursini et al. investigating the cytotoxic effects of MWCNTs on the respiratory system, two different types of MWCNTs were used (Ursini et al., 2014). The cytotoxic effects of pristine and carboxyl MWCNTs were tested on lung alveolar epithelial cells (A549) and bronchial epithelial cells (BEAS-2B) using the water-­ soluble tetrazolium assay (WST1) and the lactate dehydrogenase (LDH) assay. It was found that MWCNTs showed no cytotoxic effect against A549 cells. In contrast, carboxyl MWCNT samples decreased cell viability and increased membrane damage of BEAS-2B cells. Another study on the toxic effect of MWCNTs on the respiratory system was conducted by Öner and coworkers (Öner et al., 2020). In this study, DNA methylation changes were examined to determine toxicity as a result of low-dose CNT exposure. For this purpose, human bronchial epithelial cells (16HBE) were treated with MWCNT and SWCNT.  After exposure, no changes in DNA methylation were observed in MWCNT-treated cells, whereas hypermethylation and hypomethylation were observed in SWCNT-treated cells. Tian et al. designed embolic microspheres with slow drug release properties as a drug delivery system (Tian et  al., 2023). They added MWCNTs to these microspheres to stabilize the spherical morphology. L929 fibroblast cells were preferred to determine the in vitro cytotoxic effects of the designed CNT-loaded microspheres. A viability/cytotoxicity assay kit was applied to L929 fibroblast cells in contact with CNT-loaded microspheres. In this study, cytotoxicity analysis showed that CNT-­ loaded microspheres were not cytotoxic. Thaher et al. incorporated CNTs into polymethyl methacrylate (PMMA) bone cement to be used in total joint replacement (Thaher et al., 2022). To determine the cytotoxicity of the prepared bone cements, MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide], LDH, and alizarin red cytotoxicity assays were performed on human osteoblast cells. The results of the cytotoxicity assays showed that there was no significant difference in cytotoxicity between bone cements with and without CNTs. CNTs have also been used in nerve repair. Nerve canals are being developed for the recovery of impaired peripheral nerves and for the efficient transmission of nerve messages. Jhang et al. designed biodegradable PVA/CNT electrospun films as nerve conduits due to the conductivity of CNT and biocompatibility of poly(vinyl alcohol) (PVA) (Jhang et al., 2022). The cytotoxic properties of the proposed neural conduit were investigated using the MTT method and L929 fibroblast cells. As a result of the research, it was observed that PVA/CNT electrospun films did not show toxic effects on cells and even increased cell viability.

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

337

Patel and colleagues created a nanocomposite material for use in cancer treatment (Patel et al., 2023). To determine the cell viability of the designed hydroxyl-­ functionalized MWCNT-reinforced PMMA nanocomposites, they were subjected to MTT assay using oral squamous carcinoma (KB cell line) cells. MTT assay showed that hydroxyl-functionalized MWCNT-reinforced PMMA nanocomposite significantly suppressed the growth of the KB cell line. The IC50 concentration against KB cells was determined to be 136  mg/ mL.  Furthermore, it was observed that intracellular reactive oxygen species (ROS) formation was significantly increased after treatment of KB cells with hydroxyl-functionalized MWCNT-­reinforced PMMA nanocomposites. In line with the results obtained, it was suggested that this nanocomposite could be used in cancer treatment. Mollania and colleagues conducted a study using CNT carrier systems in the treatment of cancer (Mollania et al., 2020). In this study, pyrimethamine, an effective drug, was adsorbed on the outer surface of SWCNT. The cytotoxicity of the SWCNT-pyrimethamine nanocarrier system was investigated by MTT assay using the MCF-7 cell line. It was found that pyrimethamine-loaded CNTs showed toxic effects and decreased cell viability as the molarity increased. Randive et al. conducted a similar study in which CNTs served as drug carriers in the treatment of cancer (Randive et al., 2021). Current drugs used to treat colon cancer also show toxic effects on non-cancerous cells. Folate receptors are overexpressed in colon cancer. Therefore, SWCNT carriers were modified with folic acid to enable targeted delivery. After the addition of folic acid, SWCNT was loaded with capecitabine to form a nanocomposite. Cytotoxicity studies of pure capecitabine and capecitabine-­loaded SWCNTs were performed using MTT and sulforhodamine B (SRB) assays. Cytotoxicity studies on COLO320DM and HT29 cell lines showed that the developed nanocomposite system gave better results compared to pure capecitabine. In addition, the in vivo study on rabbits showed that the system was successfully developed to provide targeted delivery of capecitabine in the colonic region. CNTs, due to their small size and high specific surface area, are considered an effective device, especially for the delivery of different therapeutic molecules. Previous studies have shown that although CNTs at low concentrations improve cell performance, CNTs used at high concentrations exhibit toxicity (Lau et al., 2022). CNTs have multifaceted toxicity effects. The toxic effects of CNTs can vary depending on several factors, including the size, surface chemistry, and concentration of the nanotubes (Shvedova et al., 2005; Thurnherr et al., 2011). Thus, the toxic effects of CNTs can potentially be utilized in applications such as induction of microbial growth and control of viral infections (Banihashemi et al., 2020; Dong et al., 2009; Rajabathar et al., 2020). Many studies have shown that SWCNTs have higher toxicity to the pathogen than MWCNTs and convincingly cause the destruction of the cell membrane of the pathogen (Saleemi et al., 2022). The toxic effects of CNTs on bacteria and viruses can vary depending on the specific properties of the nanotubes and the target microorganism.

338

A. M. Allahverdiyev et al.

Antimicrobial and Antiviral Characteristics of CNTs Antibacterial Mechanism Various toxicity mechanisms for CNT antibacterial activities have been reported, such as cell membrane destruction, physical piercing, disruption of metabolic processes, and oxidative stress caused by direct oxidation of cell organelles and secondary oxidation of cellular phospholipids by ROS (Deryabin et al., 2010; Kang et al., 2007, 2008a, b). The basic mechanism highlighted by all studies is that disruption of the cellular membrane of the experimental microorganism leads to cellular content leaking and the loss of the viability of bacteria (Azizi-Lalabadi et al., 2020). Kang et al. provided the first direct proof that bacterial cell mortality was most likely caused by cell membrane disruption caused by direct interaction with SWCNTs (Kang et  al., 2007). A multitude of research concluded that SWCNTs cause cell membrane damage. Furthermore, some research discovered that an hour of interaction of SWCNTs and Escherichia coli (E. coli) bacteria was sufficient to cause membrane damage, but others discovered that a substantially longer treatment period (up to days) was necessary to achieve the same outcome. Various investigations have seen the physicsal interactions between the side/end section of CNTs and bacteria membranes. Investigations demonstrated that the ends of SWCNTs interacted with the Salmonella bacterial membrane (Kang et al., 2007, 2008a, b). E. coli cells exposed to implanted SWCNTs for an hour experienced severe membrane damage and disrupted cellular stability. Membrane damage caused intracellular component leakage, which was confirmed by the efflux of considerably more plasmid DNA and RNA into the solution of E. coli cells treated with SWCNTs in comparison to the control solution of bacteria. However, MWCNT treatment did not result in considerable efflux of plasmid DNA and RNA into solution, confirming that SWCNTs demonstrated far more efficient antibacterial action against E. coli cells than MWCNTs. SWCNTs had the strongest antibacterial action against microbial species of any carbon-based nanostructured materials tested, including MWCNTs, fullerenes, and colloidal graphite. Oxidative stress generation is another significant mechanism. CNTs can produce ROS, which can disrupt bacterial DNA, proteins, and lipids, resulting in cell death (Deline et al., 2020; Peng et al., 2021; Pulskamp et al., 2007). CNTs and C60 are both members of the fullerene family and are made completely of carbon atoms. Fullerene C60 toxicity has been proven to be mostly induced by oxidative stress on microorganisms. Adjustments in the expression of oxidative stress-related genes were identified using DNA microarray assays after E.coli bacteria were treated with SWCNTs and MWCNTs. Approximately, half of the genes increased following superoxide-generating substance exposure showed a more than double increase after CNT treatment. After bacterial contact to SWCNTs and MWCNTs, multiple genes of the soxRS and oxyR complexes, which are associated with microbial oxidative stress responses, were activated and expressed (Maksimova et  al., 2023; Rajabathar et al., 2020).

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

339

Alterations were also found in a group of genes associated to cell envelope integrity, as well as many stress-related gene pathways. These findings demonstrated that oxidative stress contributes to CNT cytotoxicity. Vecitis et  al. established for the first time that SWCNT antibacterial actions are reliant on electronic properties (for example, metallic vs superconducting materials) (Vecitis et al., 2010). Researchers selected well-characterized SWCNTs with equal diameter and length but a different percentage of metallic nanotubes. The vitality of Escherichia coli was shown to decrease when the proportion of metallic SWNTs increased. Time-dependent cytotoxicity tests revealed that the bulk of the SWNT antimicrobial effect occurred within 15 min after bacteria-SWNT interaction in all circumstances. In vitro SWNT-­ mediated oxidation of glutathione, a major intracellular thiol that functions as an antioxidant and redox status mediator, was used to examine the SWNT toxicity mechanism. The degree of glutathione oxidation was shown to rise as the proportion of metallic SWNTs increased, indicating an increased role for oxidative stress. Others, on the other hand, have observed that oxidative stress from nanotubes is not the primary cause of cellular damage. Liu et al. examined the oxidation reduction potentials (OPR) of SWCNTs, the elimination of thiol groups (SH) on protein structures both within and outside of cell membranes from SWCNT-exposed E. coli and Bacillus subtilis cells, and the oxidation of a free protein bovine serum albumin (BSA) by SWCNTs (Liu et al., 2009). The findings indicated that when SWCNTs were dispersed individually, they exhibited greater toxicity towards various bacteria (including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis) compared to when they formed aggregates. When SWCNTs were dispersed individually, they appeared as numerous dynamic “nano darts” within the solution, consistently targeting the bacteria. This led to the deterioration of bacterial cell integrity and eventual cell death. The controlled experiments conducted indicated that cell growth inhibition and oxidative stress were not the primary factors contributing to cell death. The absence of BSA oxidization by SWCNTs implies that the proteins on the bacterial membrane are unlikely to undergo oxidation when exposed to SWCNTs. While the potential contribution of oxidative stress induced by SWCNTs to their antibacterial activity cannot be completely ruled out, it appears to have a minor role in the context of this study. Furthermore, the notable disparities in physical and chemical properties between SWCNTs and C60 suggest significant differences in their toxicity profiles. The varying outcomes observed in different studies can be attributed to the distinctive characteristics of SWCNTs, particularly their large aspect-to-diameter ratios, which give rise to behavior resembling that of nano-darts. Many investigations have found that CNT adherence to bacteria is the primary cause of the antibacterial action. CNTs, on the other hand, have been shown to bind to the surface of Streptococcus mutans (S. mutans) via entanglement without causing microbial cell membrane damage (Akasaka & Watari, 2009). The scanning electron microscopy analysis revealed that bundles of SWCNTs and thin MWCNTs with a diameter of around 30 nm exhibited a moderate level of flexibility. These nanotubes were observed to readily wrap around the curved surface of S. mutans (Akasaka & Watari, 2009). Simon-Deckers et al. conducted a study using transmission electron microscopy (TEM) to investigate the adsorption of bacteria

340

A. M. Allahverdiyev et al.

(Cupriavidus metallidurans or E. coli) onto MWCNTs. Their findings indicated that CNTs can cause protein dysfunction and DNA damage in the adsorbed bacteria (Simon-Deckers et al., 2009). The interaction between CNTs and DNA can result in the disruption of DNA structure, primarily through the occurrence of single-strand breaks. Additionally, CNTs have the potential to impact the stacking of DNA bases and induce conformational changes in DNA molecules. In general, nanomaterials exhibit antimicrobial effects by disrupting bacterial cell membranes or by penetrating membranes and specifically targeting intracellular components such as proteins, RNA, and DNA (Singha et al., 2017). However, it should be noted that CNTs can also have an indirect contact with DNA without actually entering the cell. This indirect contact occurs through secondary effects, such as the generation of ROS when CNTs interact with the cellular environment. The ROS produced can interact with DNA, leading to structural changes and hindering the DNA repair mechanisms (Wang et al., 2016). Additionally, CNTs have a tendency to bind to the side chains of amino acids and thiol (SH) groups in proteins, which can alter their electrical properties (Lynch & Dawson, 2008). Furthermore, metallic catalytic residues, such as nickel, that are present throughout the production process can be found in CNTs (Saleemi et  al., 2022). This transition metal, especially nickel, takes part in the Fenton reaction, which produces hydroxyl radicals that react with protein molecules. Initially, it was considered that these catalytic metal residues were to fault for CNT toxicity to human or animal cells. However, later research has demonstrated that the presence of catalytic metal residues in CNTs is not highly connected to their toxicity to bacterial cells. Kang et al. discovered that MWCNTs with nearly little catalytic metal concentration had somewhat greater toxicity than dry oxidized MWCNTs with moderate quantities of iron (Kang et al., 2008a, b). Similarly, Liu et al. reported that CNT antibacterial capabilities were unaffected by cobalt residues in SWCNTs (Liu et al., 2009). The disparities in these experiments might be related to differences in the metal concentration of the CNT samples or distinct physicochemical alterations caused during different treatment methods. It is also feasible that leftover catalytic metals influence eukaryotic cell lines via mechanisms that are unaffected in bacterial models (DONG et al., 2012).

Antiviral Characteristics Antiviral agents are divided into two classes: virostatic and virucidal. Virostatic agents suppress the growth and replication of viruses (effective in the early stages of infection by reducing the rate of viral replication through a binding mechanism), while virucidal ones have a lethal effect on viruses and have a permanent effect. Since antiviral substances are nano-sized, they interact with viruses at the nano level. Carbon nanomaterials (carbon quantum dots, fullerene, CNT and graphene oxide) are among the potential antiviral agents due to their physical, chemical and electrical properties (Hassan et al., 2020).

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

341

CNTs have aroused great interest in recent years among nanomaterials that have been discovered to possess antiviral properties. The antiviral effect of CNT material is greatly influenced by the properties of this nanomaterial such as size, length, diameter, surface functionality. The antiviral activity of CNTs is based on several mechanisms that target the structure of viruses, causing structural damage to the membrane and inhibiting the replication of the virus (Kang et al., 2007, 2008a, b). In 2014, Navanietha Krishnaraj et  al. examined the molecular interaction of CNTs with three key target proteins of the human immunodeficiency virus (HIV) virus. As a result, they found that CNTs have a high binding affinity to these proteins. These interactions proved the effectiveness of CNTs in targeting HIV-­ mediated retroviral infections (Navanietha Krishnaraj et al., 2014). In another study, porphyrin, a potent antiviral agent, was conjugated with MWCNTs porphyrin-­ conjugated multi-walled carbon nanotubes (NT-P). Since CNTs can be recovered from the solution by filtration, they were used as tissue scaffolds. In the presence of visible light, NT-P were reported to significantly reduce the ability of Influenza A virus to infect mammalian cells (Banerjee et  al., 2012). These studies show that biocompatible, low toxicity CNTs have the potential to inhibit RNA-type viruses. COVID-19 In recent years, novel coronaviruses have periodically emerged in different parts of the world (Li et  al., 2020). The severe acute respiratory syndrome coronavirus (SARS-­CoV) emerged in 2002. During the outbreak, it reportedly infected 8422 people worldwide and caused 916 deaths. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was also first identified in 2012. It is also reported to have infected a total of 1401 MERS-CoV people, 543 of which resulted in death. Coronavirus disease 2019 (COVID-19) is a highly contagious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After the first cases of this predominantly respiratory viral disease were first reported in Wuhan, Hubei Province, China in late December 2019, SARS-CoV-2 spread rapidly around the world in a short period of time. This forced the World Health Organization (WHO) to declare it a global pandemic on 11 March 2020. Globally, as of April 12, 2023, there have been 762,791,152 confirmed cases of COVID-19, including 6,897,025 deaths reported to WHO (WHO, 2023, https://covid19.who. int/,Cascella et al., 2023 ; Msemburi et al., 2023). Coronavirus Definition and Characteristics SARS-CoV-2, an enveloped and single-stranded RNA virus, is 30  kb long and encodes four major structural proteins, including spike (S), envelope (E), membrane (M) and nucleocapsid (N). SARS-CoV-2 belongs to the β-Coronavirus family, which is in the same family as middle east respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV (Yu et al., 2023).

342

A. M. Allahverdiyev et al.

SARS-CoV-2 infection is reported to spread rapidly through respiratory droplets produced during sneezing and coughing. The virus binds to host receptors in the host. It then invades cells by endocytosis or membrane fusion. The S protein of the virus binds to Angiotensin-converting enzyme 2 (ACE2) receptors in the host pulmonary epithelium and then the viral contents are released into the host cell. Once viral RNA reaches the nucleus, it uses RNA polymerase to amplify negative stranded RNA from a single stranded positive RNA template (single strand positive RNA, ssRNA). Simultaneously, viral mRNA enables the formation of new viral proteins and particles, which are then transferred to other cells (Varghese et al., 2022). Coronaviruses (CoVs) are becoming a constant threat to human health as they emerge periodically and unpredictably, spread rapidly and cause serious infectious diseases. This is especially true when there are no approved vaccines or drugs for the treatment of CoV infections and when there are various animal reservoirs for CoVs and recombinant CoVs. The high rate of spread of SarS-CoV-2 infection that emerged in 2019 has led to the need to develop new methods or materials for diagnosis, treatment and inactivation. Accurately tracking the impact of COVID-19 has been fraught with challenges, especially until the WHO declared it a pandemic in March 2020. One of the biggest initial challenges has been to develop diagnostic tools to accurately identify the presence of the virus (Msemburi et al., 2023; Cascella et al., 2023).  arbon Nanomaterials in the Prevention, Diagnosis, and Treatment C of SARS-CoV-2 Infection CNTs play an important role in the detection of target molecules in clinical and pharmaceutical fields, especially when they are present in trace amounts in biological fluids. Due to their high mechanical strength, flexibility, fine pore size, low density, large surface area, electrical conductivity, etc., CNTs can transmit physical or chemical interactions, especially those generated in sensing systems. They are also resistant to most acids, bases and respiratory droplets, biocompatible with various drugs, and capable of forming ROS (Pacurari et  al., 2012; Yang et  al., 2015). SWCNTs and MWCNTs, known as folded graphene sheets with lengths ~50–1000 nm and diameters ~5–20 nm, are useful nanomaterials for the detection, inactivation or filtering of biological components (Rashid et al., 2017). In the fight against viral systems, they have been used in the diagnosis, viral protein detection and drug delivery systems of viruses such as influenza, SARS-CoV-1, SARS-CoV-2 and HIV (Aasi et al., 2020). The binding of CNTs with ssRNA in the genetic material of SARS-CoV-2 infection helps drug delivery. Furthermore, CNTs coupling with the hACE2 (human angiotensin-converting enzyme-2) receptor helps to produce better masks and PPE (personal protective equipment) and diagnostic kits (Varghese et al., 2022). Quantitative reverse transcription-polymerase chain reactions (qRT-PCRs), a molecular method, detect nucleic acids by amplifying specific genetic sequences of viral genomes (Smyrlaki et  al., 2020). It has been reported that this diagnostic

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

343

method used in medical institutions is time-consuming and requires laboratory-­ based hospitals, making it difficult to control the virus, especially in regions with poor infrastructure. For this reason, low-cost methods that do not require special facilities and can provide faster results are needed (Kim et al., 2022). In addition, methods involving immunological analysis (Enzyme Linked Immunosorbant Assay - ELISA) have disadvantages due to the need for complex production of antibodies and recombinant proteins (Sheikhzadeh et al., 2020). Identifying and then isolating infected people was an important step in the fight against COVID-19. Controlling the outbreak could only be possible with an accurate and rapid diagnosis. This is where the use of biosensors played an important role. Nanomaterials have contributed to the development of new biosensors with their unique properties or functionalization. Biosensors are known as analytical techniques that function as effective, real-­ time and simple tools for the detection of some infectious diseases. Biosensors are known as techniques invented by biotechnologists and used to detect bacteria or viruses by recognizing the properties of biomarkers or targets (Abid et al., 2021). Biosensors consist of three main components: bioreceptor, transducer and signal processing system. The bioreceptor component can be nucleic acids (DNA, RNA), monoclonal antibodies, glycan, lectin enzymes and tissue or whole cell. These components interact specifically with a biomarker (toxins, pesticides, drug metabolites, bacteria, viruses, metals, etc.). The transducer converts these interactions into a measurable signal (optical, mass-based, magnetic, thermometric, electrochemical). Qualitative or quantitative identification of the pathogen, recording and visualization of the signals are then followed and reported (Perumal et al., 2014; Scott et al., 2015; Vidic et al., 2017). Improvements are provided by nanotechnology-based interventions in the development of biosensors. In particular, the characteristic properties (physical, chemical, mechanical, electrical, magnetic, etc.) of various nanomaterials such as CNTs, carbon quantum dots (QDs), gold (Au) and other metallic-nanoparticles are exploited to emphasize their biosensing ability (Mokhtarzadeh et  al., 2017). Due to the high prevalence of the COVID-19 outbreak, the tools used in its detection were insufficient at first. However, there is a need for diagnostic tools that are more sensitive, selective, robust, fast and accurate in their biosensing properties. Accordingly, studies on the development of various CNT-based biosensors for the prevention, diagnosis and treatment of SARS-CoV-2 infection have increased, as shown in Fig. 2. In general, CoVs have specific physical and chemical properties, such as being acid-intolerant or sensitive to heat. CoVs are inactivated when exposed to ultraviolet light (UV) at 254 nm or in a strongly acidic environment or when exposed to 56 °C for 30 min (Darnell et al., 2004; Weiss et al., 2005). However, since CoVs are sensitive to restriction nucleic acid lyase, they have been exploited in the development of biosensors or personal protective equipment. CNTs have been used in personal protective equipment (masks, etc.) due to their good photothermal conversion capacity and superior near-infrared light absorption. These properties make it possible to sterilize infected protective equipment by heating, near infrared laser irradiation or UV. In addition, it shows that they can be used in various theranostic applications.

344

A. M. Allahverdiyev et al.

Fig. 2  Schematic representation of the antiviral applications of CNTs-based materials in the prevention, detection, and treatment of CoVs and other viral infections

RNA-lyase-coupled acidified modified/conjugated CNTs have been developed to exploit the photothermal conversion capacity of CNTs for the inhibition and elucidation of SARS-CoV-2 (Yang et al., 2020). It is thought that these and similar studies may guide the designs to be developed in the fight against SARS-CoV-2. In another study, a CNT field-effect transistor (FET) based biosensor was developed for the detection of SARS-CoV-2. The sensor was fabricated by fixing the reverse sequence of the RNA-dependent polymerase gene of SARS-CoV-2 to the CNT channel and tested for synthetic positive and control target sequences. Showing a selective detection response to the positive target sequence with a limit of detection (LOD) of 10 fM (femtometer, 10–15), the sensor showed promise as a diagnostic tool for SARS-CoV-2 (Thanihaichelvan et al., 2022). During and after SARS-CoV-2 spread rapidly and became a global problem, diagnostic kits and tests were needed, especially for faster and more reliable tests for its diagnosis. Their availability is known to be critical in curbing the pandemic. Shao et al. also used a high-purity semiconductor SWCNT-based FET to detect the presence of SARS-CoV-2  in clinical nasopharyngeal samples. SWCNT FET sensors with functionalization of anti-SARS-CoV-2 Spike protein antibody (SAb) and antinucleocapsid protein antibody were reported to detect S and N antigen, reaching a detection limit of 0.55 fg/mL for S antigen (SAg) and 0.016 fg/mL for N antigen (NAg) in calibration samples (Shao et al., 2021) The SAb-functionalized FET sensors developed in this study performed well in distinguishing between positive and negative samples. They also demonstrated that it can be used as a low-cost, rapid COVID-19 antigen diagnostic tool with high analytical sensitivity and specificity.

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

345

With the increasing need for nucleic acid diagnostic kits with COVID-19, low-­ cost materials that can be an alternative to consumables used in diagnostic kits have been considered. In this process, Jeong et al. developed a modular method using ssDNA-bound SWCNTs for highly efficient extraction of viral nucleic acids. With this method, ssDNA bound to CNTs can bind to the viral RNA of the target SARS-­ CoV-­2 by hybridization and be separated from the liquid phase with a single-tube system for downstream RT-qPCR detection with minimal use of chemical reagents. Extraction of the target SARS-CoV-2 RNA was performed with 100% yield in phosphate buffered saline using the nanotube-based extraction method compared to 20% yield using commercial silica-column kits. They found that CNTs provide 50% extraction directly from salivary fluid with similar efficiency to commercial DNA/RNA extraction kits. Accordingly, they reported that there is no need for some steps in commercial kits (Jeong et al., 2021). CNTs have attracted the attention of scientists for vaccine delivery and vaccine release because their surface charge can be adjusted and they have a large surface area. In vaccine applications, the surfaces of CNTs are replaced with antigens to create an immune response with the right specificity while maintaining their own properties. Thanks to their large surface area, they can be transferred into cells along with large amounts of antigens. This has been reported to make CNTs an ideal candidate for vaccine development against COVID-19. In this context, CNTs need to be conjugated and functionalized with biologically targeted molecules (sugar, glycolipid, protein, RNA and DNA) (Hassan et al., 2019; Rahamathulla et al., 2021). In another study, molecular mechanics simulations were investigated to examine the molecular interaction of carbon nanoparticles (CNPs) with RNA fragments of SARS-CoV-2. It was found that the interaction affinity of CNPs with the RNA fragment of SARS-CoV-2 increased in the order CNT>graphene>fullerene. Moreover, the first quantitative structure-activity relationships (QSAR) models, a useful tool to investigate nanotechnology effects on SARS-CoV-2, showed robustness and high agreement on the energies of CNPs interactions with the RNA fragment (Zhang et al., 2021). Although this study is known as the first QSAR study, it is thought that these relationship models will provide convenience in investigating the interactions of nanomaterials with other viruses. Most pathogens use heparan sulfate in the extracellular matrix of cells to regulate hemostasis as a means to reach and adhere to cells. The mucosal layer, such as the respiratory tract, contains polysaccharide structures, including natural products of heparan sulfate. Therefore, heparin, an analogue of the proteoglycans of heparan sulfate, is used as a receptor (biotransducer) in biosensors (Mycroft-West et  al., 2020). Wasik et  al. developed a heparin-functionalized SWCNT-based chemical resistant biosensor for the detection of dengue virus, an RNA virus (Wasik et al., 2017). In this study, heparin was used for the first time instead of antibody as a biotransducer. In addition, the biosensor sensitivity was found to be within the clinically relevant range. In addition, when the interaction of the S protein of SARS-­CoV-­2 with heparin is examined, there is a disorder/conformational shift during binding. However, heparin-functionalized CNTs were thought to be effective in the development of SARS-CoV-2 therapies (Mycroft-West et al., 2020).

346

A. M. Allahverdiyev et al.

SARS-CoV-2 infection spreads through droplets after sneezing and coughing. To prevent further spread, personal protective equipment such as masks are used. Due to the different sizes between viruses (⁓30–140 nm), fabric pore sizes are an important parameter for this mask to be effective (Zhu et al., 2020a, b). Developing materials or methods that enable surfaces to capture or neutralize viruses can reduce the risk of transmission. Since conventional masks with large pore size cannot filter viruses, it was thought that nanomaterials could be utilized. By integrating these large surface area nanomaterials with sustainable fabrics, the idea is that they can be effective for the capture, detection and inactivation of viruses. At the same time, studies were advanced with the idea that drugs or disinfectants could be included in this integration (Leung et al., 2020; Zhu et al., 2020a, b). Lee et al. developed a CNT-based face mask filter against COVID-19 virus. CNT filter masks are stronger and more durable than conventional masks, more uniform, more hydrophobic, and a superior barrier due to their high thermal conductivity. While breathability is the same as conventional polypropylene, the pore size is smaller than the size of a coronavirus due to the tightly woven network of CNTs. Moreover, aerosol-synthesized CNT filters are thought to facilitate the fight against the COVID-19 pandemic due to their easy processability, low cost, light weight and applicability, while at the same time, they produce hyperthermic antiviral effects that offer better protection against the virus and reusability due to their superior thermal conductivity (Lee et al., 2021). Surface Modifications In the literature, it has been reported in some in vitro studies that an increase in the infectivity of H1N1 virus in lung epithelial cells was observed after intranasal administration of CNTs (Sanpui et al., 2014). The toxicity of CNTs in intranasal applications as a perspective in the fight against COVID-19 may limit their use. In particular, they can be transported to the lungs via the respiratory tract, activating macrophages and causing pulmonary fibrous and collagen formation in the lesions. However, it is reported to bind to the epidermal growth factor receptor (EGFR) receptor and provide instant uptake (provided by instant internalization) by lung epithelial cells (Luanpitpong et al., 2014; Maruyama et al., 2015). It is thought that the cytotoxicity of CNTs on lung tissue can be reduced by functionalizing their surfaces with different polymers or proteins. It has been reported that conjugation of CNTs with hyaluronic acid greatly increases their interaction with bronchial cells and prevents the inflammatory cascade since macrophages in the alveoli do not engulf CNTs (Hussain et  al., 2016). Functionalization with cellular ligands also increases the uptake of CNTs by cells (by endocytic absorption), suggesting that they can be used as carriers for drug release into target tissue. The use of CNTs could be crucial in the diagnosis, treatment and theranostics of SARS-CoV-2 infection. However, in general, CNTs may not be recommended for use in the diagnosis and prevention of the virus in COVID-19-related studies, while their use in treatment regimens may not be recommended due to the inability to overcome the limitations described above.

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

347

Recent Studies on Antimicrobial and Antiviral Applications Latest Literature on Antibacterial Applications CNTs are highly versatile nanomaterials that have gained significant attention in the development of antibacterial interfaces (Saliev, 2019). Their antibacterial activity is influenced by several parameters, including their content and surface characteristics (Abbasi et al., 2022). Factors such as the length, size, and the number of graphene sheets present on the CNTs play a crucial role in determining their effectiveness against bacteria (Baek et  al., 2019; Saleemi et  al., 2022). Numerous studies have focused on exploring the antibacterial properties of both SWCNTs and MWCNTs, shedding light on their potential applications in combating bacterial infections. These studies have investigated the mechanisms by which CNTs exert their antibacterial effects, as well as the factors that influence their performance as antibacterial agents (Rajabathar et al., 2020). In the following paragraphs, we will delve into recent articles that provide detailed insights into the antibacterial properties of SWCNTs and MWCNTs, highlighting their potential for various antibacterial applications. The antibacterial activity of SWCNTs, in particular, has been the subject of recent studies aiming to elucidate their effectiveness against a wide range of bacterial strains (Luo et al., 2020; Masoumeh et al., 2022; Rajabathar et al., 2020; Zhu et  al., 2020a, b). Pristine SWCNTs possess inherent antibacterial properties, but their effectiveness can be further enhanced through functionalization, where specific chemical groups are attached to their surface (Kumar et al., 2019; Masoumeh et al., 2022; Noor et al., 2020). This modification allows for tailored interactions with bacterial cells, leading to enhanced antibacterial activity (Alavi et al., 2021). Recent studies have focused on investigating the antibacterial properties of both pristine and functionalized SWCNTs, aiming to unravel their mechanisms of action and explore their potential in the development of novel antibacterial strategies (Cajero-Zul et al., 2019; Chaudhari et al., 2019; Goodwin et al., 2015; Sah et al., 2018). Using a human three-dimentional (3D) skin model, Chaudhari et al. investigated the cytotoxicity and antibacterial properties of antimicrobial peptide-­ functionalized Ag-coated SWCNT against Staphylococcus infection (Chaudhari et  al., 2019). The aim was to examine skin development on scaffolds and create functionalized Ag-coated CNTs with antimicrobial peptides using carboxylated Ag-coated CNTs. They used bacterial enumeration and scanning electron microscopy (SEM) to analyze the cytotoxicity of the CNTs as well as their antimicrobial efficacy against Staphylococcus aureus. The results indicated that the functionalized CNTs were non-toxic to skin cells and successfully inhibited bacterial growth when compared to untreated skin. SEM analysis verified the presence of Staphylococcus aureus on the non-treated skin but not on the treated skin. These results imply that functionalized Ag-coated SWCNTs have the potential to be non-­ toxic antimicrobial agents, which might aid in the development of innovative antibacterial skin replacements.

348

A. M. Allahverdiyev et al.

Another study done by Goodwin et al. evaluated the effect of CNT loading and form on the contacts between Pseudomonas aeruginosa bacteria and PVA nanocomposites incorporating oxidized SWCNTS (O-SWCNTs) and MWCNTs (O-MWCNTs) (Goodwin et al., 2015). Despite being oxidized, the incorporation of O-SWCNTs or O-MWCNTs in nanocomposites resulted in antibacterial characteristics on the surfaces. The proportion of live cells fell exponentially as CNT loading increased, with O-SWCNTs being more toxic. The overall area of contact between bacteria and CNTs corresponded with the toxicity of CNT surfaces. Dead cells, on the other hand, may protect living cells from the cytotoxicity of CNTs, allowing biofilm development on CNT-containing nanomaterials exposure to Pseudomonas aeruginosa for extended periods of time. Such results emphasize the complicated interactions between CNTs and microorganisms, as well as the consequences for antibacterial capabilities and biofilm development on CNT-containing nanocomposites. Sah et al. conducted research, which was focused on creating a nanocomposite made of SWCNTs and amine-functionalized porphyrin for antibacterial research employing photodynamic antibacterial chemotherapy (Sah et  al., 2018). When exposed to light waves, the SWCNT-porphyrin conjugates displayed the capacity to disrupt bacterial cell membranes, showing their viability as antimicrobial compounds. The composition and antibacterial capabilities of the nano-composite were confirmed using field emission SEM (FE-SEM), TEM, and fluorescence microscopy. The prospective of SWCNT-aminoporphyrin conjugates as an effective antimicrobial agent is highlighted throughout this study. In another research by Cajero-Zul et al. functionalized CNTs were incorporated into a polymeric matrix composed of star-shaped poly(ε-caprolactone) (stPCL) and poly (ethylene glycol) (PEG) to create nanocomposites (Cajero-Zul et al., 2019). Spectroscopic characterization tests indicated that CNTs functionalized with hydroxyl, carboxyl, and acyl chloride groups were effectively linked to the stPCL-­ PEG copolymer. The crystallization mechanism of the nanocomposites varied according on the functionalized CNTs concentration, demonstrating either nucleation or anti-nucleation properties. When compared to the pure polymer matrix, the nanocomposites had a greater Young’s modulus and thermal stability. Nevertheless, they were shown to be less resistant to the development of Staphylococcus aureus and Pseudomonas aeruginosa than the pure polymer matrix. These discoveries provide light on the antibacterial characteristics of CNT-based nanocomposites, as well as their prospective uses in the combat against bacterial infections. The study done by Sapkota et al. presents a promising approach to enhance the antibacterial properties of SWCNTs through the synthesis of stable heterojunction nanocomposites with copper (II) oxide (CuO) (Sapkota et al., 2020). The bactericidal activity of these nanocomposites is proven by extensive evaluation with the broth-dilution technique and growth-inhibition-zone analysis. The results show that the antibacterial action is strong, with significant decreases in bacterial colonies and the establishment of obvious inhibitory zones. Remarkably, the CuO-SWCNT composite treated at 500  °C for 5  h outperforms pure CuO on Staphylococcus aureus(S. aureus) and E.coli, creating inhibitory zones 182% and 162% bigger,

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

349

correspondingly. These results indicate the strong antimicrobial properties of SWCNT-­CuO nanocomposites. Luo et al. investigated the potential of SWCNTs as antimicrobial nanomaterials by exploiting unique cationic surfactants derived from cardanol, a product of cashew nut shell liquid (Luo et al., 2020). SWCNTs are efficiently dispersed in aqueous solutions by these surfactants due to strong π-stacking interactions. Cardanol-­derived surfactants outperform frequently used surfactants in terms of SWCNT dispersion, resulting in dramatically increased antibacterial action. SWCNT dispersion in these surfactants demonstrate minimal inhibitory concentrations of 0.33  μg/mL against E.coli and 0.02 μg/mL against S. aureus at a concentration of 0.5 wt%. The improved dispersion of SWCNTs and the positively charged ions produced by the hydrophilic heads of the surfactants, that engage with the oppositely charged surfaces of bacteria, are linked to this exceptional antibacterial action. The use of cardanol-­derived surfactants offers great potential in allowing a variety of SWCNT applications, providing an efficient and sustainable alternative to antimicrobial therapies. Due to their remarkable physicochemical features, MWCNTs have emerged as a potential nanomaterial in this sector (Saleemi et al., 2022). Recent studies suggest that MWCNTs have strong antibacterial efficacy against a wide variety of microorganisms, making them a particularly important tool in the combat against drug-­ resistant bacteria. In a study by Mondal et al. copper nanoparticles produced from fish bile juice were used to coat MWCNTs (Mondal & Mondal, 2023). The resultant nanocomposite material showed substantial antibacterial effect against both S. aureus and P. aeruginosa, having a Minimum inhibitory concentration (MIC) of 24 g/mL and 16 g/mL, respectively. In order to understand the process of bacterial toxicity, comprehensive research was conducted. Furthermore, the nanomaterial displayed outstanding antibiofilm characteristics against the relevant bacterial strains. These results show that the produced nanocomposite has the potential to be an effective antimicrobial and antibiofilm agent that can target both Gram-positive and Gram-negative pathogenic bacteria. Furthermore, the nanocomposite demonstrated good hemocompatibility performance, making it a viable option for biomedical applications. It should be noted that the greener production technique employing fish bile juice offers a unique approach. In research done by Stegarescu et al., four typical bacterial strains were used to test the antibacterial efficacy of different nanocomposite materials based on functionalized MWCNTs (Stegarescu et al., 2022). Metal oxide (CuO and NiO) nanoparticles and antibiotics (azithromycin and ciprofloxacin) were integrated with MWCNTs to establish the nanocomposite materials. S. aureus and Enterococcus faecalis, two Gram-positive, and E. coli and P. aeruginosa, two Gram-negative bacteria, were used to test the antibacterial effect of multiple compositions of these nanomaterials. The most efficient nanocomposites against all bacterial strains were those functionalized with ciprofloxacin, demonstrating that the addition of Cu and Ni decreased the efficacy of ciprofloxacin. The antimicrobial activity of ciprofloxacin-­ functionalized nanocomposites was also superior than that of azithromycin-­functionalized nanocomposites. These results improve the research

350

A. M. Allahverdiyev et al.

on the antibacterial characteristics of nanocomposite materials and provide guidance for the next environmental pollution research. Moreover, in the field of wastewater treatment, MWCNTs have received substantial interest in recent years due to their antibacterial characteristics. These investigations have shown that MWCNTs may efficiently limit the proliferation and propagation of numerous microorganisms in wastewater systems, even drug-­ resistant bacteria (Manimegalai et  al., 2023; Mousavi & Janjani, 2020; Nasrollahzadeh et al., 2021). Because of their distinct physicochemical properties and powerful antimicrobial performance, they are a promising candidate for improving the efficiency and effectiveness of wastewater treatment systems, thereby addressing the growing concerns about microbiological pathogens and resistant bacteria in water resources. Asadi et al. synthesized nanocomposite membranes for the treatment of wastewater that are highly antimicrobial and antifouling (Asadi et al., 2022). MWCNTs that have been chlorophyll(a) and silver ion functionalized (MWCNT-Chl(a)-Ag) were embedded into the polyvinylidene fluoride (PVDF) membranes. Various procedures were used to characterize the surface and bulk characteristics of the composite nanomaterials. The manufactured membranes had lower water contact angles, higher total porosity, and higher pure water flux. In terms of flux recovery ratio, the MWCNT-Chl(a)-Ag/PVDF nanocomposites surpassed pristine PVDF membranes and demonstrated outstanding antimicrobial and antifouling capabilities. The inhibitory zone approach was used to assess the antimicrobial activities of the nanocomposites, and the analysis revealed that they have high antibacterial effects over E.coli. The research sheds light on how to enhance water treatment by modifying PVDF membranes with functionalized MWCNTs. In another research related to wastewater treatment, Khalatbary et al. focused on the antibacterial characteristics of MWCNTs coated with silver nanoparticles (AgNPs) (Khalatbary et al., 2022). When coupled with γ-Fe2O3, they may be magnetically retrieved from wastewater. The researchers created a new nanocomposite material, γ-Fe2O3/MWCNT/Ag, by utilizing a sustainable and ecologically friendly procedure that used waste tires and Viscum album leaves extract. The nanocomposite showed enhanced antimicrobial activities against Gram-positive bacteria as well as outstanding adsorption capability for the elimination of sulfamethazine (SMT) from aqueous solutions. The antibacterial activity of the nanocomposite was tested using the Agar-well diffusion technique, and it showed inhibitory zones both against Gram-negative (E.coli) and Gram-positive (S.aureus) bacteria. This demonstrates the potential of γ-Fe2O3/MWCNT/Ag combined nanocomposite material as an excellent antimicrobial agent for wastewater treatment. The goal of the study done by Hassani et al. is to create a novel nano-antibiotic by covalently grafting levofloxacin (LVX) onto MWCNTs (Hassani et al., 2022). In comparison to P. aeruginosa, the antibiotic-CNT nanocomposite showed improved in  vitro antibacterial efficacy against S aureus. Additionally, it showed a pH-­ sensitive release profile and a high drug loading capacity. The nano-antibiotic demonstrated strong bactericidal action against S. aureus in an in vivo rodent wound infection model. The findings show that conjugating the medication with surface-­ modified MWCNTs improved its antibacterial capabilities, making them a suitable

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

351

nanocarrier for LVX in the treatment of wound infections. In order to decrease side effects and boost treatment efficacy, the study emphasizes the viability of MWCNTs as a controlled release and delivery mechanism for medication. The study by Pargami et al. examines the antibacterial properties of carboxyl-­ functionalized MWCNTs (MWCNT-COOH) against Mycobacterium fortuitum, a pathogen noted for its drug resistance (Pargami et  al., 2022). MWCNT-COOH nanofluid displayed antibacterial activity against Mycobacterium fortuitum and significantly decreased bacterial resistance to drugs, including kanamycin and streptomycin. The method of action includes MWCNT-COOH penetrating the cell wall of bacteria. The data imply that MWCNT-COOH has the ability to be used as a viable method for combating Mycobacterium fortuitum antibiotic-resistant infections. For spinal cord regeneration and repair, in a study done by Wang et al., a multifunctional polycitrate-based nanocomposite hydrogel (PMEAC) scaffold incorporating MWCNT is established (Wang et  al., 2022). This scaffold has biomimetic mechanical and electrical characteristics comparable to spinal cord tissue, as well as injectability, self-healing capability, tissue adhesiveness, wide ranging antimicrobial qualities, and UV-shielding capability. In vitro tests show antimicrobial effectiveness against E. coli, S. aureus, and multi-drug resistant S. aureus (MRSA), as well as UV-shielding capabilities. The composite hydrogel is also cytocompatible, hemocompatible, and biodegradable. The PMEAC scaffold enhances locomotor recovery, decreases inflammation, and facilitates remyelination and axonal regeneration in vivo in a spinal cord lesion model. The antibacterial features of the hydrogel reduce infection risks and its UV-shielding performance offer potential uses in wound healing. Furthermore, the PMEAC hydrogel has fluorescence and photothermal capabilities, which allow for in  vivo monitoring, photothermal antimicrobial treatment, and cancer photothermal therapy. Huang et al. used a chimeric protein named MPKE to improve the dispersibility of MWCNTs in aqueous conditions (Huang et al., 2021). Remarkable dispersibility properties in water, alkaline solutions, and organic solvents were demonstrated by the MPKE-MWCNTs. The modified MWCNTs showed substantial reduction rates when used as carriers for silver nanoparticles (AgNPs) in wastewater treatment. The MPKE-MWCNTs further demonstrated biocompatibility, antimicrobial activities, and the capacity to prevent the growth of E. coli and S. aureus pathogens. AgNPs were thought to have harmed bacterial macromolecules and cellular membranes, which is what provided the antimicrobial properties. Even after extensive preservation, the AgNPs-MPKE-MWCNTs continued to have an antibacterial effect, demonstrating their potential for use in wastewater treatment technologies. In the research done by Laganà et al., bacterial strains obtained from hospital-­ acquired illnesses were tested for their susceptibility to MWCNTs’ antibacterial properties (Laganà et al., 2021). At concentrations of 50 and 100 g mL−1, pristine and functionalized MWCNTs were both examined, and the findings indicated that MWCNTs have growth-inhibiting properties, with functionalized MWCNTs showing a stronger impact than pristine MWCNTs. Depending on what type of bacteria and how susceptible they were to antibiotics, the inhibitory impact changed. Gram-­ positive bacteria that are resistant to cell wall antibiotics had a longer-lasting

352

A. M. Allahverdiyev et al.

inhibitory impact, whereas Gram-negative bacteria that had resistance to nucleic acid and protein synthesis inhibitors only showed a transient effect. These results demonstrate the link between MWCNT efficacy and antimicrobial resistance. According to the study, functionalized MWCNTs have the potential to serve as carriers for bioactive antimicrobial compounds, but their use would need to establish both patient safety and the lack of toxicity.

Recent Work on Antiviral Applications A review of the literature reveals that there are very few studies on the use of CNTs in the treatment of viral infections. In addition to their antiviral activity, CNTs are also involved in the targeted delivery of antiviral drugs. CNTs used as drug delivery systems reduce drug toxicity and increase the duration of drug efficacy (He et al., 2013; Jain, 2012). Although CNT-based filters are known to be effective in the removal of viral and bacterial pathogens, Vecitis et al. developed an anodic filter using MWCNT for the removal and inactivation of E. coli and MS2 virus. This filter is reported to increase the sensitivity in the determination of the number of bacteria and viruses in wastewater at applied potentials of 2 and 3 V. At the same time, at these voltages, it was found to inactivate more than 96.6% of the adsorbed viruses and more than 75% of the eliminated bacteria in the last 30 s of filtration (Vecitis et al., 2011). When SWCNTs were decorated with a metal (Pt, Pd, Ni, Cu, Rh, or Ru) to design their surfaces and evaluated for the adsorption of hydrogen peroxide, which is harmful for many viruses, the following were observed: (i) physically absorbed, albeit weakly, on SWCNT in the presence of a single H2O2; (ii) Rh-SWCNT and Ru-SWCNT adsorbates showed high performance in H2O2 adsorption; and (iii) Pt-SWCNT and Cu-SWCNT systems showed a very long shelf life. Considering their properties, such as virus removal and inactivation, it has been reported that these systems may be candidate systems for use in personal protection equipment design (Aasi et al., 2020). The antiviral properties of different CNT derivatives were investigated by Gupta et al. (Gupta et al., 2021). In the study, antiviral properties of CNT, graphene oxide (GO), reduced graphene oxide (rGO), hybrid GO-CNT, rGO-CNT, and CNTs functionalized with carboxylic (CNT-COOH), phenol (CNT-phenol), silver (CNT-Ag) were investigated. E. coli and MS2 bacteriophages were used as a model virus to determine the antiviral activity of nanocarbons. All nanocarbon groups showed antiviral effect against the virus. GO and rGO showed the least effect, while functionalized derivatives of CNTs showed the highest effect. Gupta et al. performed a similar study on different hybrid structures (Gupta et al., 2022). In this study, the antiviral effects of CNTs, metal oxides (MO), and hybrid structures (MO-CNTs) against E. coli and MS2 bacteriophage were investigated. As a result of the study, MO-CNTs showed the highest antiviral effect and metal oxides showed the lowest effect. In both studies, hybrid CNTs were more effective due to the synergistic mechanism.

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

353

This mechanism includes the physical damage of the viruses by trapping them by CNTs and the toxicity effect of other groups incorporated into the hybrid structure. In the study by Zhang and coworkers, CNTs were evaluated as inhibitors. HIV-1 integrase (IN) enzyme plays an important role in the replication process of HIV-1. It is an important molecule targeted for drugs used in the treatment of AIDS. In this study, the binding and inhibition of CNT to HIV-1 IN were investigated by the simulation method. The results showed that CNT acts as an allosteric inhibitor by binding stably to HIV-1 IN. In addition, Zhang et al. also emphasized that CNTs can be used as drug carriers in HIV treatment. CNTs, which have been investigated for their usability in antiviral therapies, have attracted considerable attention, especially their effectiveness as HIV inhibitors. The interaction of CNTs with viral enzymes and acting as HIV inhibitors was studied by Iannazzo colleagues (Iannazzo et al., 2015). Since CNTs with hydrophobic structure have low dispersibility in water, oxidized MWCNTs (ox-MWCNTs) exhibiting hydrophilic properties were used in this study. Ox-MWCNT with high hydrophilicity showed very good antiviral properties. It was concluded that the antiviral properties of MWCNTs conjugated with various therapeutic drugs were compatible with their hydrophilicity. Another study in which CNTs served as carriers in acquired immune deficiency syndrome (AIDS) treatment was conducted by Pandey et al. (Pandey et al., 2021). Karanjin, an effective therapeutic molecule against HIV, was transported to the target site by CNTs. Good results were obtained from the interaction of karanjin with CNT. Thanks to these results, it is thought that more effective drug delivery studies will be carried out in the future. The effects of respiratory syncytial virus (RSV) on the respiratory tract after CNT exposure were investigated by Boyoglu and colleagues (Boyoglu, 2010). RSV is an important pathogen causing lower respiratory tract infections and pneumonia in children. In the study, Hep-2 and Vero cells were treated with CNTs and silver coated CNTs and the inhibition effect of nanoparticles on RSV was evaluated. MTT assay was used to determine the cell viability percentage of both cell lines incubated with different concentrations of CNTs. The results of the study show that CNTs and silver-coated CNTs can inhibit RSV infection. A similar study was conducted by Chen et al. but with different results (Chen et al., 2017). Male C57BL/6 mice were used in this in vivo study. Mice were first exposed to SWCNT and then to influenza A virus. After 7 days, mRNA expression of antiviral and inflammatory genes was measured in euthanized mice. The data show that SWCNTs remained in mouse lungs throughout the experiment and suppressed antiviral gene expression. Therefore, it is concluded that SWCNT exposure induces suppression of respiratory viral infection. When vaccine-related studies of CNTs are examined, they are usually combined with immunogenic proteins of the target virus. This combination is observed to have a longer duration of protection. At the same time, since the studies are generally related to aquatic viruses, the target host is also aquatic organisms. Most studies suggest that the vaccines developed are effective, but the relationship between SWCNTs and the immune system needs to be thoroughly investigated. Koi herpesvirus (KHV) virus is known as a threatening pathogen in carp production. In a study,

354

A. M. Allahverdiyev et al.

a plasmid expression vector for KHV ORF14, an immunogenic gene of this virus, was ligated to SWCNTs to develop an anti-KHV vaccine. This vaccine was reported to provided 81.9% protection against intraperitoneal challenge with KHV. In this study, it was proved that when DNA was given together with SWCNTs, the duration of protection was longer than that of naked DNA. It was thought that this new vaccine could provide an effective method to deal with KHV disease (Hu et al., 2020). A vaccine candidate using SWCNTs was developed against Micropterus Salmoides rhabdovirus (MSRV) virus, which poses a significant threat to sea bream and sea bass. In the study, SWCNTs were combined with the glycoprotein (G) of the virus. After 28 days of inoculation with G or SWCNTs-G, fish were administered a lethal dose of MSRV. As a result, SWCNTs increased the protection rate by 30.6% and were considered to be a promising immersion subunit vaccine candidate against MSRV-induced mortality. It has also been proposed as a solution to use epitopes to increase the efficacy of the vaccine (Guo et al., 2020). The studies mentioned above show that some types of CNTs have antiviral properties and can suppress the infection of various viruses. It was also concluded that the antiviral properties depend on the type of CNT used. However, this is still an emerging area of research and more work needs to be done. Further understanding of the antiviral activities of CNTs may enable the development of future nanotechnology-­based antiviral therapies.

Future Use According to recent studies, SWCNTs and MWCNTs have the potential to be used in antibacterial and antimicrobial applications in the future. Whole review research indicated that both pristine and functionalized MWCNTs have the potential to serve as carriers for bioactive antimicrobial agents. However, before they can be put into practice, it is critical to assure patient safety by resolving toxicity issues. More research and improvements in nanotechnology will be required to determine the efficacy, safety, and regulatory factors related with the usage of SWCNTs and MWCNTs in antimicrobial therapy. The methods and designs to be developed for effective inhibition/inactivation of the virus should focus on the physical and chemical properties of the viruses as well as the properties of the materials to be used. We need to strengthen focus and research in this area. They can be used in the design of high-sensitivity materials that can be an alternative to commercial diagnostic kits, which are costly, slow to supply and limited in number. In any other possible pandemic, the speed of spread can be prevented by rapid detection of infection. Especially with the COVID-19 pandemic, the use of nanomaterials in biosensing systems developed for the detection of RNA viruses has increased. The use of nanotechnology in the evaluation of clinical findings has

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

355

provided higher reliability, sensitivity, and reproducibility in the results obtained, while at the same time providing economic relief. Candidate materials or bioactive molecules that can be used to functionalize the surfaces of CNTs, which have many properties, can be investigated to reduce limitations in order to ensure their use in treatment.

Conclusion Infectious diseases caused by bacteria and viruses are increasing their spread all over the world day by day. Our world is at risk of encountering many pandemics that may be caused by microorganisms that threaten human life, just like in the COVID-19 pandemic. Pandemics, which cause the death of millions of people around the world and cause socioeconomic problems in many countries, cause great harm to the development of countries. Drug resistance, which microorganisms have developed rapidly in recent years, is the biggest obstacle in front of human beings in the fight against these infections. For this reason, it is of great importance to make new breakthroughs in the health system both in order to eliminate existing drug resistance and to prevent pandemics such as COVID-19. The developments in nanotechnology have been a beacon of hope for the development of innovative, high value-added and successful products in the field of health. CNTs constitute one of the most important opportunities offered by nanotechnology to our age. Their unique physical, mechanical, and electrical properties enable CNTs to be used successfully in areas such as drug development against infectious agents, production of vaccine candidates and the production of diagnostic kits. In this review, recent studies on the use of CNTs in antimicrobial and antiviral applications are summarized. Elimination of possible toxicities of CNTs, production of more effective antibacterial/antiviral platforms with surface modifications, and increasing their usability as drug delivery systems will further increase the use of these nanomaterials in the field of health. In particular, the fact that they have extremely large surface areas and contain different reactive groups on the surface contributes to the use of CNTs with many antimicrobial agents. In this way, it is possible to increase the existing antimicrobial activities of CNTs and to develop nanosystems that will show stronger therapeutic efficacy. These properties also help the use of CNTs as vaccine carrier platforms that carry different antigens and can be highly active in stimulating the immune system. In addition to all these, CNTs can also be used to develop fast and reliable diagnostic kits that can be used to identify infectious agents that are difficult to diagnose. As can be seen, CNTs have a great importance in the development of drugs, diagnostic kits, and vaccine candidates in the health sector and in the use of these products in the fight against diseases. We think that with the increase in in vivo studies and clinical trials in this field in the future, the touches that CNTs have made on our lives will increase even more.

356

A. M. Allahverdiyev et al.

References Aasi, A., Aghaei, S. M., Moore, M. D., & Panchapakesan, B. (2020). Pt-, Rh-, Ru-, and Cu-single-­ wall carbon nanotubes are exceptional candidates for design of anti-viral surfaces: A theoretical study. International Journal of Molecular Sciences, 21(15), 5211. Abbasi, F., Hajilary, N., & Rezakazemi, M. (2022). Antibacterial properties of MXene-based nanomaterials: A review. Materials Express, 12(1), 34–48. https://doi.org/10.1166/MEX.2022.2138 Abdulhameed, A., & Halim, M.  M. (2023). Electrical and thermal conductivity enrichment by carbon nanotubes: A mini-review. Emergent Materials, 1, 1–12. https://doi.org/10.1007/ S42247-­023-­00499-­8 Abid, S. A., Muneer, A. A., Al-Kadmy, I. M., Sattar, A. A., Beshbishy, A. M., Batiha, G. E. S., & Hetta, H. F. (2021). Biosensors as a future diagnostic approach for COVID-19. Life Sciences, 273, 119117. Akasaka, T., & Watari, F. (2009). Capture of bacteria by flexible carbon nanotubes. Acta Biomaterialia, 5(2), 607–612. https://doi.org/10.1016/J.ACTBIO.2008.08.014 Alavi, M., Jabari, E., & Jabbari, E. (2021). Functionalized carbon-based nanomaterials and quantum dots with antibacterial activity: A review. Expert Review of Anti-Infective Therapy, 19(1), 35–44. https://doi.org/10.1080/14787210.2020.1810569 Allahverdiyev, A. M., Kon, K. V., Abamor, E. S., Bagirova, M., & Rafailovich, M. (2011). Coping with antibiotic resistance: Combining nanoparticles with antibiotics and other antimicrobial agents. Expert Review of Anti-Infective Therapy, 9(11), 1035–1052. https://doi.org/10.1586/ ERI.11.121 Årdal, C., Balasegaram, M., Laxminarayan, R., McAdams, D., Outterson, K., Rex, J.  H., & Sumpradit, N. (2019). Antibiotic development—Economic, regulatory and societal challenges. Nature Reviews Microbiology, 18(5), 267–274. https://doi.org/10.1038/s41579-­019-­0293-­3 Arun, H. (2021). Advancements in the use of carbon nanotubes for antenna realization. AEU  International Journal of Electronics and Communications, 136, 153753. https://doi. org/10.1016/J.AEUE.2021.153753 Asadi, A., Gholami, F., Nazari, S., & Dolatshah, M. (2022). Preparation of antifouling and antibacterial polyvinylidene fluoride membrane by incorporating functionalized multiwalled carbon nanotubes. Journal of Water Process Engineering, 49, 103042. https://doi.org/10.1016/J. JWPE.2022.103042 Azizi-Lalabadi, M., Hashemi, H., Feng, J., & Jafari, S. M. (2020). Carbon nanomaterials against pathogens; the antimicrobial activity of carbon nanotubes, graphene/graphene oxide, fullerenes, and their nanocomposites. Advances in Colloid and Interface Science, 284, 102250. https://doi.org/10.1016/J.CIS.2020.102250 Baek, S., Joo, S. H., Su, C., & Toborek, M. (2019). Antibacterial effects of graphene- and carbon-­ nanotube-based nanohybrids on Escherichia coli: Implications for treating m ­ ultidrug-­resistant bacteria. Journal of Environmental Management, 247, 214. https://doi.org/10.1016/J. JENVMAN.2019.06.077 Baghel, P., Sakhiya, A.  K., & Kaushal, P. (2022). Ultrafast growth of carbon nanotubes using microwave irradiation: Characterization and its potential applications. Heliyon, 8(10), e10943. https://doi.org/10.1016/J.HELIYON.2022.E10943 Bai, Y., Park, I. S., Lee, S. J., Bae, T. S., Watari, F., Uo, M., & Lee, M. H. (2011). Aqueous dispersion of surfactant-modified multiwalled carbon nanotubes and their application as an antibacterial agent. Carbon, 49(11), 3663–3671. https://doi.org/10.1016/J.CARBON.2011.05.002 Banerjee, I., Douaisi, M. P., Mondal, D., & Kane, R. S. (2012). Light-activated nanotube–porphyrin conjugates as effective antiviral agents. Nanotechnology, 23(10), 105101. Banihashemi, K., Sobouti, B., Mehregan, I., Bakhtiari, R., & Amirmozafari, N. (2020). The construction of carbon nanotubes containing an anti-bacterial chemical component and its effect on MDR and XDR isolates of pseudomonas aeruginosa. Reports of Biochemistry & Molecular Biology, 9(1), 89. www.RBMB.net

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

357

Bao, L., Cui, X., Mortimer, M., Wang, X., Wu, J., & Chen, C. (2023). The renaissance of one-­ dimensional carbon nanotubes in tissue engineering. Nano Today, 49, 101784. https://doi. org/10.1016/J.NANTOD.2023.101784 Boyd, N.  K., Teng, C., & Frei, C.  R. (2021). Brief overview of approaches and challenges in new antibiotic development: A focus on drug repurposing. Frontiers in Cellular and Infection Microbiology, 11, 442. https://doi.org/10.3389/FCIMB.2021.684515/BIBTEX Boyoglu, S., Adiani, L., Boyoglu, C., Mishra, M., Rangari, V., Dennis, V., & Singh, S. R. (2010). CNTs and Silver coated CNTs provide immune responses against RSV. Cajero-Zul, L. R., López-Dellamary, F. A., Gómez-Salazar, S., Vázquez-Lepe, M., Vera-Graziano, R., Torres-Vitela, M. R., Olea-Rodríguez, M. A., & Nuño-Donlucas, S. M. (2019). Evaluation of the resistance to bacterial growth of star-shaped poly(ε-caprolactone)-co-poly(ethylene glycol) grafted onto functionalized carbon nanotubes nanocomposites. Journal of Biomaterials Science. Polymer Edition, 30(3), 163–189. https://doi.org/10.1080/09205063.2018.1558487 Cascella, M., Rajnik, M., Aleem, A., Dulebohn, S., & Di Napoli, R. (2023). Features, evaluation, and treatment of coronavirus (COVID-19). StatPearls. Castenholz, R.  W. (2015). General characteristics of the cyanobacteria. Bergey’s Manual of Systematics of Archaea and Bacteria, 1, 23. https://doi.org/10.1002/9781118960608. CBM00019 Chaudhari, A. A., Joshi, S., Vig, K., Sahu, R., Dixit, S., Baganizi, R., Dennis, V. A., Singh, S. R., & Pillai, S. (2019). A three-dimensional human skin model to evaluate the inhibition of Staphylococcus aureus by antimicrobial peptide-functionalized silver carbon nanotubes. Journal of Biomaterials Applications, 33(7), 924–934. https://doi.org/10.1177/0885328218814984 Chen, H., Zheng, X., Nicholas, J., Humes, S. T., Loeb, J. C., Robinson, S. E., ... & Sabo-Attwood, T. (2017). Single-walled carbon nanotubes modulate pulmonary immune responses and increase pandemic influenza a virus titers in mice. Virology journal, 14, 1–15. Darnell, M. E., Subbarao, K., Feinstone, S. M., & Taylor, D. R. (2004). Inactivation of the coronavirus that induces severe acute respiratory syndrome, SARS-CoV. Journal of Virological Methods, 121(1), 85–91. Deline, A.  R., Frank, B.  P., Smith, C.  L., Sigmon, L.  R., Wallace, A.  N., Gallagher, M.  J., Goodwin, D.  G., Durkin, D.  P., & Howard Fairbrother, D. (2020). Influence of oxygen-­ containing functional groups on the environmental properties, transformations, and toxicity of carbon nanotubes. Chemical Reviews, 120(20), 11651–11697. https://doi.org/10.1021/ACS. CHEMREV.0C00351/ASSET/IMAGES/MEDIUM/CR0C00351_M017.GIF Delves, P. J., Martin, S. J., Burton, D. R., & Roitt, I. M. (2017). Roitt’s essential immunology (13th ed.). John Wiley & Sons. Deryabin, D. G., Vasilchenko, A. S., Aleshina, E. S., Tlyagulova, A. S., & Nikiyan, H. N. (2010). An investigation into the interaction between carbon-based nanomaterials and Escherichia coli cells using atomic force microscopy. Nanotechnologies in Russia, 5(11), 857–863. https://doi. org/10.1134/S1995078010110169/METRICS Dong, L., Witkowski, C.  M., Craig, M.  M., Greenwade, M.  M., & Joseph, K.  L. (2009). Cytotoxicity effects of different surfactant molecules conjugated to carbon nanotubes on human astrocytoma cells. Nanoscale Research Letters, 4(12), 1517–1523. https://doi.org/10.1007/ S11671-­009-­9429-­0/FIGURES/3 Dong, X., Tang, Y., Lilly, M., Aferchıch, K., & Yang, L. (2012). Antimicrobial effects of carbon nanotubes. Materials Science, Environmental Science, Chemistry, 2(04), 1230012. https://doi. org/10.1142/S1793984412300129 dos Santos Ramos, M.  A., dos Santos, K.  C., da Silva, P.  B., de Toledo, L.  G., Marena, G.  D., Rodero, C.  F., de Camargo, B.  A. F., Fortunato, G.  C., Bauab, T.  M., & Chorilli, M. (2020). Nanotechnological strategies for systemic microbial infections treatment: A review. International Journal of Pharmaceutics, 589, 119780. https://doi.org/10.1016/J. IJPHARM.2020.119780 Gacem, A., Modi, S., Yadav, V. K., Islam, S., Patel, A., Dawane, V., Jameel, M., Inwati, G. K., Piplode, S., Solanki, V. S., & Basnet, A. (2022). Recent advances in methods for synthesis of carbon nanotubes and carbon nanocomposite and their emerging applications: A descriptive review. Journal of Nanomaterials, 2022, 1. https://doi.org/10.1155/2022/7238602

358

A. M. Allahverdiyev et al.

Garg, A., Chalak, H. D., Belarbi, M. O., Zenkour, A. M., & Sahoo, R. (2021). Estimation of carbon nanotubes and their applications as reinforcing composite materials — An engineering review. Composite Structures, 272, 114234. https://doi.org/10.1016/J.COMPSTRUCT.2021.114234 Gong, H., Peng, R., & Liu, Z. (2013). Carbon nanotubes for biomedical imaging: The recent advances. Advanced Drug Delivery Reviews, 65(15), 1951–1963. https://doi.org/10.1016/J. ADDR.2013.10.002 Goodwin, D. G., Marsh, K. M., Sosa, I. B., Payne, J. B., Gorham, J. M., Bouwer, E. J., & Fairbrother, D. H. (2015). Interactions of microorganisms with polymer nanocomposite surfaces containing oxidized carbon nanotubes. Environmental Science and Technology, 49(9), 5484–5492. https:// doi.org/10.1021/ACS.EST.5B00084/SUPPL_FILE/ES5B00084_SI_001.PDF Guo, Z. R., Zhao, Z., Zhang, C., Jia, Y. J., Qiu, D. K., Zhu, B., & Wang, G. X. (2020). Carbon nanotubes-loaded subunit vaccine can increase protective immunity against rhabdovirus infections of largemouth bass (Micropterus Salmoides). Fish & Shellfish Immunology, 99, 548–554. Gupta, I., Azizighannad, S., Farinas, E. T., & Mitra, S. (2021). Antiviral properties of select carbon nanostructures and their functionalized analogs. Materials Today Communications, 29, 102743. Gupta, I., Azizighannad, S., Farinas, E. T., & Mitra, S. (2022). Synergistic Antiviral Effects of Metal Oxides and Carbon Nanotubes. International Journal of Molecular Sciences, 23(19), 11957. Hassan, H.  A. F.  M., Diebold, S.  S., Smyth, L.  A., Walters, A.  A., Lombardi, G., & Al-Jamal, K. T. (2019). Application of carbon nanotubes in cancer vaccines: Achievements, challenges and chances. Journal of Controlled Release, 297, 79–90. Hassan, A. A., Mansour, M. K., El Ahl, R. M. S., El Hamaky, A. M., & Oraby, N. H. (2020). Toxic and beneficial effects of carbon nanomaterials on human and animal health. In Carbon nanomaterials for agri-food and environmental applications (pp. 535–555). Elsevier. Hassan, S., Nadeem, A. Y., Qaiser, H., Kashif, A. S., Ahmed, A., Khan, K., & Altaf, A. (2023). A review of carbon-based materials and their coating techniques for biomedical implants applications. Carbon Letters, 2023, 1–18. https://doi.org/10.1007/S42823-­023-­00496-­1 Hassani, M., Tahghighi, A., Rohani, M., Hekmati, M., Ahmadian, M., & Ahmadvand, H. (2022). Robust antibacterial activity of functionalized carbon nanotube- levofloxacine conjugate based on in vitro and in vivo studies. Scientific Reports, 12(1), 10064. https://doi.org/10.1038/ S41598-­022-­14206-­W He, H., Pham-Huy, L. A., Dramou, P., Xiao, D., Zuo, P., & Pham-Huy, C. (2013). Carbon nanotubes: applications in pharmacy and medicine. BioMed research international, 2013. Herrera-Ramirez, J.  M., Perez-Bustamante, R., & Aguilar-Elguezabal, A. (2018). An overview of the synthesis, characterization, and applications of carbon nanotubes. Carbon-Based Nanofillers and Their Rubber Nanocomposites: Carbon Nano-Objects, 1, 47–75. https://doi. org/10.1016/B978-­0-­12-­813248-­7.00002-­X Hetta, H. F., Ramadan, Y. N., Al-Harbi, A. I., Ahmed, A., Battah, B., Abd Ellah, N. H., Zanetti, S., & Donadu, M. G. (2023). Nanotechnology as a promising approach to combat multidrug resistant bacteria: A comprehensive review and future perspectives. Biomedicines, 11(2). https:// doi.org/10.3390/BIOMEDICINES11020413 Holmes, E.  G., & Rambaut, A. (2004). Viral evolution and the emergence of SARS coronavirus. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 359(1447), 1059–1065. https://doi.org/10.1098/RSTB.2004.1478 Holmes, B., Fang, X., Zarate, A., Keidar, M., & Zhang, L. G. (2016). Enhanced human bone marrow mesenchymal stem cell chondrogenic differentiation in electrospun constructs with carbon nanomaterials. Carbon, 97, 1–13. https://doi.org/10.1016/J.CARBON.2014.12.035 Hu, F., Li, Y., Wang, Q., Wang, G., Zhu, B., Wang, Y., et al. (2020). Carbon nanotube-based DNA vaccine against koi herpesvirus given by intramuscular injection. Fish & Shellfish Immunology, 98, 810–818. Huang, J., Sui, X., Qi, H., Lan, X., Liu, S., & Zhang, L. (2021). Zwitterionic peptide-functionalized highly dispersed carbon nanotubes for efficient wastewater treatment. Journal of Materials Chemistry B, 10(14), 2661–2669. https://doi.org/10.1039/D1TB02348A Huo, M., Wang, L., Chen, Y., & Shi, J. (2020). Nanomaterials/microorganism-integrated microbiotic nanomedicine. Nano Today, 32, 100854. https://doi.org/10.1016/J.NANTOD.2020.100854

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

359

Hussain, S., Ji, Z., Taylor, A. J., DeGraff, L. M., George, M., Tucker, C. J., et al. (2016). Multiwalled carbon nanotube functionalization with high molecular weight hyaluronan significantly reduces pulmonary injury. ACS Nano, 10(8), 7675–7688. Iannazzo, D., Pistone, A., Galvagno, S., Ferro, S., De Luca, L., Monforte, A.  M., Da Ros, T., Hadad, C., Prato, M., & Pannecouque, C. (2015). Synthesis and anti-HIV activity of carboxylated and drug-conjugated multi-walled carbon nanotubes. Carbon, 82(C), 548–561. https://doi. org/10.1016/J.CARBON.2014.11.007 Jackson, P., Jacobsen, N.  R., Baun, A., Birkedal, R., Kühnel, D., Jensen, K.  A., Vogel, U., & Wallin, H. (2013). Bioaccumulation and ecotoxicity of carbon nanotubes. Chemistry Central Journal, 7(1), 1–21. https://doi.org/10.1186/1752-­153X-­7-­154/FIGURES/4 Jain, K. K. (2012). Advances in use of functionalized carbon nanotubes for drug design and discovery. Expert opinion on drug discovery, 7(11), 1029–1037. Jain, A.  K., Mehra, N.  K., Lodhi, N., Dubey, V., Mishra, D.  K., Jain, P.  K., & Jain, N.  K. (2009). Carbon nanotubes and their toxicity, 1(3), 167–197. https://doi.org/10.1080/ 17435390701639688 Jeong, S., González-Grandío, E., Navarro, N., Pinals, R.  L., Ledesma, F., Yang, D., & Landry, M. P. (2021). Extraction of viral nucleic acids with carbon nanotubes increases SARS-CoV-2 quantitative reverse transcription polymerase chain reaction detection sensitivity. ACS Nano, 15(6), 10309–10317. Jhang, J.-C., Lin, J.-H., Lou, C.-W., & Chen, Y.-S. (2022). Biodegradable and conductive PVA/ CNT nanofibrous membranes used in nerve conduit applications, 51(1S), 1048–1065. https:// doi.org/10.1177/15280837211032086 Kandhola, G., Park, S., Lim, J.  W., Chivers, C., Song, Y.  H., Chung, J.  H., Kim, J., & Kim, J.  W. (2023). Nanomaterial-based scaffolds for tissue engineering applications: A review on graphene, carbon nanotubes and nanocellulose. Tissue Engineering and Regenerative Medicine, 2023, 1–23. https://doi.org/10.1007/S13770-­023-­00530-­3 Kang, S., Pinault, M., Pfefferle, L. D., & Elimelech, M. (2007). Single-walled carbon nanotubes exhibit strong antimicrobial activity. Langmuir: The ACS Journal of Surfaces and Colloids, 23(17), 8670–8673. https://doi.org/10.1021/LA701067R Kang, S., Herzberg, M., Rodrigues, D. F., & Elimelech, M. (2008a). Antibacterial effects of carbon nanotubes: Size does matter! Langmuir: The ACS Journal of Surfaces and Colloids, 24(13), 6409–6413. https://doi.org/10.1021/LA800951V Kang, S., Mauter, M.  S., & Elimelech, M. (2008b). Physicochemical determinants of multiwalled carbon nanotube bacterial cytotoxicity. Environmental Science & Technology, 42(19), 7528–7534. https://doi.org/10.1021/ES8010173 Khalatbary, M., Sayadi, M.  H., Hajiani, M., Nowrouzi, M., & Homaeigohar, S. (2022). Green, sustainable synthesis of γ-Fe2O3/MWCNT/Ag Nano-composites using the Viscum album leaf extract and waste car tire for removal of sulfamethazine and bacteria from wastewater streams. Nanomaterials, 12(16). https://doi.org/10.3390/NANO12162798 Kharlamova, M. V., & Kramberger, C. (2021). Applications of filled single-walled carbon nanotubes: Progress, challenges, and perspectives. Nanomaterials (Basel), 11(11), 2863. https://doi. org/10.3390/NANO11112863 Kim, S. Y., Lee, J. C., Seo, G., Woo, J. H., Lee, M., Nam, J., et al. (2022). Computational method-­ based optimization of carbon nanotube thin-film Immunosensor for rapid detection of SARS-­ CoV-­2 virus. Small Science, 2(2), 2100111. Kumar, A., Dalal, J., Dahiya, S., Punia, R., Sharma, K. D., Ohlan, A., & Maan, A. S. (2019). In situ decoration of silver nanoparticles on single-walled carbon nanotubes by microwave irradiation for enhanced and durable anti-bacterial finishing on cotton fabric. Ceramics International, 45(1), 1011–1019. https://doi.org/10.1016/J.CERAMINT.2018.09.280 Laganà, P., Visalli, G., Facciolà, A., Ciarello, M.  P., Laganà, A., Iannazzo, D., & Di Pietro, A. (2021). Is the antibacterial activity of multi-walled carbon nanotubes (Mwcnts) related to antibiotic resistance? An assessment in clinical isolates. International Journal of Environmental Research and Public Health, 18(17). https://doi.org/10.3390/IJERPH18179310

360

A. M. Allahverdiyev et al.

Lau, Z. L., Low, S. S., Ezeigwe, E. R., Chew, K. W., Chai, W. S., Bhatnagar, A., Yap, Y. J., & Show, P. L. (2022). A review on the diverse interactions between microalgae and nanomaterials: Growth variation, photosynthetic performance and toxicity. Bioresource Technology, 351, 127048. https://doi.org/10.1016/J.BIORTECH.2022.127048 Lee, S., Nam, J. S., Han, J., Zhang, Q., Kauppinen, E. I., & Jeon, I. (2021). Carbon nanotube mask filters and their hydrophobic barrier and hyperthermic antiviral effects on SARS-CoV-2. ACS Applied Nano Materials, 4(8), 8135–8144. Lekshmi, G., Sana, S. S., Nguyen, V. H., Nguyen, T. H. C., Nguyen, C. C., Van Le, Q., & Peng, W. (2020). Recent Progress in carbon nanotube polymer composites in tissue engineering and regeneration. International Journal of Molecular Sciences, 21(17), 6440. https://doi. org/10.3390/IJMS21176440 Leung, N.  H., Chu, D.  K., Shiu, E.  Y., Chan, K.  H., McDevitt, J.  J., Hau, B.  J., et  al. (2020). Respiratory virus shedding in exhaled breath and efficacy of face masks. Nature Medicine, 26(5), 676–680. Li, G., Fan, Y., Lai, Y., Han, T., Li, Z., Zhou, P., et al. (2020). Coronavirus infections and immune responses. Journal of Medical Virology, 92(4), 424–432. Liu, S., Wei, L., Hao, L., Fang, N., Chang, M. W., Xu, R., Yang, Y., & Chen, Y. (2009). Sharper and faster “nano darts” kill more bacteria: A study of antibacterial activity of individually dispersed pristine single-walled carbon nanotube. ACS Nano, 3(12), 3891–3902. https://doi.org/10.1021/ NN901252R Luanpitpong, S., Wang, L., & Rojanasakul, Y. (2014). The effects of carbon nanotubes on lung and dermal cellular behaviors. Nanomedicine, 9(6), 895–912. Luksiene, Z. (2005). New approach to inactivation of harmful and pathogenic microorganisms by photosensitization. Food Technology and Biotechnology, 43(4), 411–418. Luo, Y., Liang, W., Ma, W., Wang, P., Zhu, T., Xue, S., Yuan, Z., Gao, H., Chen, Y., & Wang, Y. (2020). Cardanol-derived cationic surfactants enabling the superior antibacterial activity of single-walled carbon nanotubes. Nanotechnology, 31(26), 265603. https://doi. org/10.1088/1361-­6528/AB7AA4 Lynch, I., & Dawson, K. A. (2008). Protein-nanoparticle interactions. Nano Today, 3(1–2), 40–47. https://doi.org/10.1016/S1748-­0132(08)70014-­8 Madigan, M., Bender, K., Buckley, D., Sattley, W. M., & Stahl, D. (2019). Brock biology of microorganisms 15th edition (2019) (pp. 261–427). Pearson. Maksimova, Y., Zorina, A., & Nesterova, L. (2023). Oxidative stress response and E. Coli biofilm formation under the effect of pristine and modified carbon nanotubes. Microorganisms, 11(5), 1221. https://doi.org/10.3390/MICROORGANISMS11051221 Manimegalai, S., Vickram, S., Deena, S. R., Rohini, K., Thanigaivel, S., Manikandan, S., Subbaiya, R., Karmegam, N., Kim, W., & Govarthanan, M. (2023). Carbon-based nanomaterial intervention and efficient removal of various contaminants from effluents – A review. Chemosphere, 312, 137319. https://doi.org/10.1016/J.CHEMOSPHERE.2022.137319 Maruyama, K., Haniu, H., Saito, N., Matsuda, Y., Tsukahara, T., Kobayashi, S., et  al. (2015). Endocytosis of multiwalled carbon nanotubes in bronchial epithelial and mesothelial cells. BioMed Research International. Masoumeh, A. M., Hamideh, R. N., Pardis, S., & Ali, K. N. R. (2022). Improving antibacterial activity of methicillin by conjugation to functionalized single-wall carbon nanotubes against MRSA. International Journal of Peptide Research and Therapeutics, 28(3). https://doi. org/10.1007/S10989-­022-­10377-­2 Meindl, C., Absenger-Novak, M., Jeitler, R., Roblegg, E., & Fröhlich, E. (2023). Assessment of carbon nanotubes on barrier function, ciliary beating frequency and cytokine release in in  vitro models of the respiratory tract. Nanomaterials, 13, 682. https://doi.org/10.3390/ NANO13040682 Miranda, C. D., Godoy, F. A., & Lee, M. R. (2018). Current status of the use of antibiotics and the antimicrobial resistance in the chilean salmon farms. Frontiers in Microbiology, 9(JUN), 1284. https://doi.org/10.3389/FMICB.2018.01284/BIBTEX

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

361

Mokhtarzadeh, A., Eivazzadeh-Keihan, R., Pashazadeh, P., Hejazi, M., Gharaatifar, N., Hasanzadeh, M., et  al. (2017). Nanomaterial-based biosensors for detection of pathogenic virus. TrAC Trends in Analytical Chemistry, 97, 445–457. Mollania, F., Hadipour, N. L., & Mollania, N. (2020). CNT-based nanocarrier loaded with pyrimethamine for adipose mesenchymal stem cells differentiation and cancer treatment: The computational and experimental methods. Journal of Biotechnology, 308, 40–55. https://doi. org/10.1016/J.JBIOTEC.2019.11.005 Mondal, A., & Mondal, N. K. (2023). Efficacy of bile juice mediated Cu@MWCNT nanostructure, with respect to antibacterial and antibiofilm activity. Materials Letters, 335, 133828. https:// doi.org/10.1016/J.MATLET.2023.133828 Mondal, T., Konda, P., Das, K., Kumar, K., & Bag, S. (2022). Evaluation of cytocompatibility as assessed by genomic stability of canine induced pluripotent stem cells propagated on carbon nanotube substrates. Indian Journal of Animal Research, 56(6), 649–654. https://doi. org/10.18805/IJAR.B-­4853 Mostafa, A. M., Mwafy, E. A., Awwad, N. S., & Ibrahium, H. A. (2021). Synthesis of multi-walled carbon nanotubes decorated with silver metallic nanoparticles as a catalytic degradable material via pulsed laser ablation in liquid media. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 626, 126992. https://doi.org/10.1016/J.COLSURFA.2021.126992 Mousavi, S. A., & Janjani, H. (2020). Antibiotics adsorption from aqueous solutions using carbon nanotubes: A systematic review. Toxin Reviews, 39(2), 87–98. https://doi.org/10.1080/1556954 3.2018.1483405 Msemburi, W., Karlinsky, A., Knutson, V., Aleshin-Guendel, S., Chatterji, S., & Wakefield, J. (2023). The WHO estimates of excess mortality associated with the COVID-19 pandemic. Nature, 613(7942), 130–137. Mycroft-West, C., Su, D., Elli, S., Li, Y., Guimond, S., Miller, G., et  al. (2020). 2019 koronavirüs (SARS-CoV-2) yüzey proteini (Spike) S1 Reseptör Bağlama Alanı, heparin bağlanması üzerine konformasyonel değişikliğe uğrar. BioRxiv, 2020–2002. Nasrollahzadeh, M., Sajjadi, M., Iravani, S., & Varma, R.  S. (2021). Carbon-based sustainable nanomaterials for water treatment: State-of-art and future perspectives. Chemosphere, 263, 128005. https://doi.org/10.1016/J.CHEMOSPHERE.2020.128005 Navanietha Krishnaraj, R., Chandran, S., Pal, P., & Berchmans, S. (2014). Hesaplamalı moleküler yaklaşım kullanılarak karbon nanotüplerin antiretroviral aktivitesi üzerine araştırmalar. Kombinatoryal Kimya ve Yüksek Verimli Tarama, 17(6), 531–535. Noor, M. M., Goswami, J., & Davis, V. A. (2020). Comparison of attachment and antibacterial activity of covalent and noncovalent lysozyme-functionalized single-walled carbon nanotubes. ACS Omega, 5(5), 2254–2259. https://doi.org/10.1021/ACSOMEGA.9B03387 Nurazzi, N.  M., Asyraf, M.  R. M., Khalina, A., Abdullah, N., Sabaruddin, F.  A., Kamarudin, S. H., Ahmad, S., Mahat, A. M., Lee, C. L., Aisyah, H. A., Norrrahim, M. N. F., Ilyas, R. A., Harussani, M. M., Ishak, M. R., & Sapuan, S. M. (2021). Fabrication, functionalization, and application of carbon nanotube-reinforced polymer composite: An overview. Polymers, 13(7), 1047. https://doi.org/10.3390/POLYM13071047 Öner, D., Ghosh, M., Coorens, R., Bové, H., Moisse, M., Lambrechts, D., Ameloot, M., Godderis, L., & Hoet, P. H. M. (2020). Induction and recovery of CpG site specific methylation changes in human bronchial cells after long-term exposure to carbon nanotubes and asbestos. Environment International, 137, 105530. https://doi.org/10.1016/j.envint.2020.105530 Ortega-Zamora, C., Jiménez-Skrzypek, G., González-Sálamo, J., Hernández-Borges, J., & González-Curbelo, M. Á. (2021). Carbon nanoparticles. Analytical Sample Preparation With Nano- and Other High-Performance Materials, 253–295. https://doi.org/10.1016/B978-0-12822139-6.00008-0 Pacurari, M., Qian, Y., Fu, W., Schwegler-Berry, D., Ding, M., Castranova, V., & Guo, N. L. (2012). Cell permeability, migration, and reactive oxygen species induced by multiwalled carbon nanotubes in human microvascular endothelial cells. Journal of Toxicology and Environmental Health, Part A, 75(2), 112–128.

362

A. M. Allahverdiyev et al.

Pandey, A.  K., Singh, V., & Dwivedi, A. (2021). Computational study of adsorption effects of Karanjin drug over carbon nanotube (C56H16) as factor of drug delivery system-A quantum chemical approach. Nano, 16(9). https://doi.org/10.1142/S179329202150106X Pargami, H.  N., Siadat, S.  D., Amiri, V., & Sheikhpour, M. (2022). Antibiotic delivery evaluation against mycobacterium fortuitum using nanofluids containing carbon nanotubes. BMC Microbiology, 22(1), 96. https://doi.org/10.1186/S12866-­022-­02523-­Z Patel, V., Joshi, U., Joshi, A., Upadhyay, T. K., Al-Keridis, L. A., & Saeed, M. (2023). Cytotoxicity analysis for the hydroxyl functionalized MWCNT reinforced PMMA nanocomposites in oral squamous carcinoma (KB) cells. Polymers, 15(5). https://doi.org/10.3390/POLYM15051192 Peng, J., He, Y., Zhou, C., Su, S., & Lai, B. (2021). The carbon nanotubes-based materials and their applications for organic pollutant removal: A critical review. Chinese Chemical Letters, 32(5), 1626–1636. https://doi.org/10.1016/J.CCLET.2020.10.026 Perumal, V., & Hashim, U. (2014). Advances in biosensors: Principle, architecture and applications. Journal of Applied Biomedicine, 12(1), 1–15. Prasek, J., Drbohlavova, J., Chomoucka, J., Hubalek, J., Jasek, O., Adam, V., & Kizek, R. (2011). Methods for carbon nanotubes synthesis—Review. Journal of Materials Chemistry, 21(40), 15872–15884. https://doi.org/10.1039/C1JM12254A Prola, L. D. T., Machado, F. M., Bergmann, C. P., de Souza, F. E., Gally, C. R., Lima, E. C., Adebayo, M. A., Dias, S. L. P., & Calvete, T. (2013). Adsorption of direct blue 53 dye from aqueous solutions by multi-walled carbon nanotubes and activated carbon. Journal of Environmental Management, 130, 166–175. https://doi.org/10.1016/J.JENVMAN.2013.09.003 Pulskamp, K., Diabaté, S., & Krug, H. F. (2007). Carbon nanotubes show no sign of acute toxicity but induce intracellular reactive oxygen species in dependence on contaminants. Toxicology Letters, 168(1), 58–74. https://doi.org/10.1016/J.TOXLET.2006.11.001 Rahamathulla, M., Bhosale, R. R., Osmani, R. A., Mahima, K. C., Johnson, A. P., Hani, U., et al. (2021). Carbon nanotubes: Current perspectives on diverse applications in targeted drug delivery and therapies. Materials, 14(21), 6707. Rahman, G., Najaf, Z., Mehmood, A., Bilal, S., Shah, A., Ul, H. A., Mian, S. A., & Ali, G. (2019). An overview of the recent Progress in the synthesis and applications of carbon nanotubes. C, 5(1), 3. https://doi.org/10.3390/C5010003 Rajabathar, J. R., Periyasamy, G., Alanazi, A. M., Govindasamy, M., & Arunachalam, P. (2020). Review on carbon nanotube varieties for healthcare application: Effect of preparation methods and mechanism insight. PRO, 8(12), 1654. https://doi.org/10.3390/PR8121654 Ramesh, M., Janani, R., Deepa, C., & Rajeshkumar, L. (2022). Nanotechnology-enabled biosensors: A review of fundamentals, design principles, materials, and applications. Biosensors, 13(1), 40. https://doi.org/10.3390/BIOS13010040 Randive, D.  S., Gavade, A.  S., Shejawal, K.  P., Bhutkar, M.  A., Bhinge, S.  D., & Jadhav, N. R. (2021). Colon targeted dosage form of Capecitabine using folic acid anchored modified carbon nanotube: In vitro cytotoxicity, apoptosis and in vivo roentgenographic study. https:// doi.org/10.1080/03639045.2021.1994988 Rashid, M. H. O., & Ralph, S. F. (2017). Carbon nanotube membranes: Synthesis, properties, and future filtration applications. Nanomaterials, 7(5), 99. Rui, H., Ting, Y., & Yan, M. Y. (2023). Advances in the application of novel carbon nanomaterials in illicit drug detection. New Journal of Chemistry, 47(5), 2161–2172. https://doi.org/10.1039/ D2NJ04816G Safarov, T., Kiran, B., Bagirova, M., Allahverdiyev, A. M., & Abamor, E. S. (2019). An overview of nanotechnology-based treatment approaches against helicobacter pylori. Expert Review of Anti-Infective Therapy, 17(10), 829–840. https://doi.org/10.1080/14787210.2019.1677464 Sah, U., Sharma, K., Chaudhri, N., Sankar, M., & Gopinath, P. (2018). Antimicrobial photodynamic therapy: Single-walled carbon nanotube (SWCNT)-porphyrin conjugate for visible light mediated inactivation of Staphylococcus aureus. Colloids and Surfaces B: Biointerfaces, 162, 108–117. https://doi.org/10.1016/J.COLSURFB.2017.11.046

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

363

Saleemi, M. A., Kong, Y. L., Yong, P. V. C., & Wong, E. H. (2022). An overview of antimicrobial properties of carbon nanotubes-based nanocomposites. Advanced Pharmaceutical Bulletin, 12(3), 449–465. https://doi.org/10.34172/APB.2022.049 Saliev, T. (2019). The advances in biomedical applications of carbon nanotubes. C, 5(2), 29. https://doi.org/10.3390/C5020029 Sanpui, P., Zheng, X., Loeb, J. C., Bisesi, J. H., Jr., Khan, I. A., Afrooz, A. R. M., et al. (2014). Single-walled carbon nanotubes increase pandemic influenza A H1N1 virus infectivity of lung epithelial cells. Particle and Fibre Toxicology, 11(1), 1–15. Sapkota, K. P., Hassan, M. M., Shrestha, S., Hanif, M. A., Islam, M. A., Akter, J., Abbas, H. G., & Hahn, J. R. (2020). Heterojunction formation between copper(II) oxide nanoparticles and single-walled carbon nanotubes to enhance antibacterial performance. International Journal of Pharmaceutics, 590, 119937. https://doi.org/10.1016/J.IJPHARM.2020.119937 Scott, K., & Yu, E. H. (Eds.). (2015). Microbial electrochemical and fuel cells: Fundamentals and applications. Woodhead Publishing. Shao, W., Shurin, M. R., Wheeler, S. E., He, X., & Star, A. (2021). Rapid detection of SARS-­ CoV-­2 antigens using high-purity semiconducting single-walled carbon nanotube-based field-­ effect transistors. ACS Applied Materials & Interfaces, 13(8), 10321–10327. Sheikhzadeh, E., Eissa, S., Ismail, A., & Zourob, M. (2020). Diagnostic techniques for COVID-19 and new developments. Talanta, 220, 121392. Shiv Charan, P.  S., Shanmugam, S., & Kamaraj, V. (2009). Transactions of the Indian ceramic society carbon nanotubes-synthesis and application carbon nanotubes-synthesis and application. Transactions of the Indian Ceramic Society, 68(4), 163–172. https://doi.org/10.108 0/0371750X.2009.11082170 Shoukat, R., & Khan, M. I. (2021). Carbon nanotubes: A review on properties, synthesis methods and applications in micro and nanotechnology. Microsystem Technologies, 27(12), 4183–4192. https://doi.org/10.1007/S00542-­021-­05211-­6/FIGURES/11 Shvedova, A. A., Kisin, E. R., Mercer, R., Murray, A. R., Johnson, V. J., Potapovich, A. I., Tyurina, Y. Y., Gorelik, O., Arepalli, S., Schwegler-Berry, D., Hubbs, A. F., Antonini, J., Evans, D. E., Ku, B. K., Ramsey, D., Maynard, A., Kagan, V. E., Castranova, V., & Baron, P. (2005). Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. American Journal of Physiology  – Lung Cellular and Molecular Physiology, 289, 33–35. https://doi.org/10.1152/AJPLUNG.00084.2005 Shvedova, A.  A., Pietroiusti, A., Fadeel, B., & Kagan, V.  E. (2012). Mechanisms of carbon nanotube-induced toxicity: Focus on oxidative stress. Toxicology and Applied Pharmacology, 261(2), 121. https://doi.org/10.1016/J.TAAP.2012.03.023 Simon, J., Flahaut, E., & Golzio, M. (2019). Overview of carbon nanotubes for biomedical applications. Materials, 12(4). https://doi.org/10.3390/MA12040624 Simon-Deckers, A., Loo, S., Mayne-L’Hermite, M., Herlin-Boime, N., Menguy, N., Reynaud, C., Gouget, B., & Carriere, M. (2009). Size-, composition- and shape-dependent toxicological impact of metal oxide nanoparticles and carbon nanotubes toward bacteria. Environmental Science & Technology, 43(21), 8423–8429. https://doi.org/10.1021/ES9016975 Singh, J., Nayak, P., Singh, G., Khandai, M., Sarangi, R. R., & Kar, M. K. (2022). Carbon nanostructures as therapeutic cargoes: Recent developments and challenges. C, 9(1), 3. https://doi. org/10.3390/C9010003 Singha, P., Locklin, J., & Handa, H. (2017). A review of the recent advances in antimicrobial coatings for urinary catheters. Acta Biomaterialia, 50, 20–40. https://doi.org/10.1016/J. ACTBIO.2016.11.070 Smyrlaki, I., Ekman, M., Lentini, A., Rufino de Sousa, N., Papanicolaou, N., Vondracek, M., et al. (2020). Massive and rapid COVID-19 testing is feasible by extraction-free SARS-CoV-2 RT-PCR. Nature Communications, 11(1), 4812. Spitalsky, Z., Tasis, D., Papagelis, K., & Galiotis, C. (2010). Carbon nanotube–polymer composites: Chemistry, processing, mechanical and electrical properties. Progress in Polymer Science, 35(3), 357–401. https://doi.org/10.1016/J.PROGPOLYMSCI.2009.09.003

364

A. M. Allahverdiyev et al.

Stegarescu, A., Lung, I., Ciorîță, A., Kacso, I., Opriș, O., Soran, M. L., & Soran, A. (2022). The antibacterial properties of nanocomposites based on carbon nanotubes and metal oxides functionalized with azithromycin and ciprofloxacin. Nanomaterials, 12(23). https://doi. org/10.3390/NANO12234115 Stout, D.  A., Durmus, N.  G., & Webster, T.  J. (2013). Synthesis of carbon based nanomaterials for tissue engineering applications. Nanomaterials in Tissue Engineering: Fabrication and Applications, 119–157. https://doi.org/10.1533/9780857097231.1.119 Sweetman, M.  J., May, S., Mebberson, N., Pendleton, P., Vasilev, K., Plush, S.  E., & Hayball, J. D. (2017). Activated carbon, carbon nanotubes and graphene: Materials and composites for advanced water purification. C, 3(2), 18. https://doi.org/10.3390/C3020018 Szabó, A., Perri, C., Csató, A., Giordano, G., Vuono, D., & Nagy, J. B. (2010). Synthesis methods of carbon nanotubes and related materials. Materials, 3(5), 3092. https://doi.org/10.3390/ MA3053092 Thanihaichelvan, M., Surendran, S. N., Kumanan, T., Sutharsini, U., Ravirajan, P., Valluvan, R., & Tharsika, T. (2022). Selective and electronic detection of COVID-19 (coronavirus) using carbon nanotube field effect transistor-based biosensor: A proof-of-concept study. Materials Today: Proceedings, 49, 2546–2549. Thaher, A., Khalil, R., Abdelghany, S., & Salem, M.  S. (2022). Antimicrobial PMMA Bone Cement Containing Long Releasing Multi-Walled Carbon Nanotubes. Nanomaterials 12(8). https://doi.org/10.3390/nano12081381 Thurnherr, T., Brandenberger, C., Fischer, K., Diener, L., Manser, P., Maeder-Althaus, X., Kaiser, J. P., Krug, H. F., Rothen-Rutishauser, B., & Wick, P. (2011). A comparison of acute and long-­ term effects of industrial multiwalled carbon nanotubes on human lung and immune cells in vitro. Toxicology Letters, 200(3), 176–186. https://doi.org/10.1016/J.TOXLET.2010.11.012 Tian, P., Liu, W., Yang, S., & Zhang, J. (2023). Amphiphilic drug slow release microspheres fabricated using polyvinyl alcohol, 10-Undecen-1-ol, and multi-walled carbon nanotubes. Journal of Applied Polymer Science, 140(7), e53498. https://doi.org/10.1002/APP.53498 Tortora, G. J., Funke, B. R., & Case, C. L. (2016). Microbiology: An introduction. Pearson. Ullah, I., Cosar, G., Abamor, E. S., Bagirova, M., Shinwari, Z. K., & Allahverdiyev, A. M. (2018). Comparative study on the antileishmanial activities of chemically and biologically synthesized silver nanoparticles (AgNPs). 3 Biotech, 8(2), 1–8. https://doi.org/10.1007/S13205-­018-­1121-­6/ FIGURES/5 Ursini, C.  L., Cavallo, D., Fresegna, A.  M., Ciervo, A., Maiello, R., Buresti, G., Casciardi, S., Bellucci, S., & Iavicoli, S. (2014). Differences in cytotoxic, genotoxic, and inflammatory response of bronchial and alveolar human Lung epithelial cells to pristine and COOH-­ functionalized multiwalled carbon nanotubes. Research Article Differences in Cytotoxic, 2014. https://doi.org/10.1155/2014/359506 Varghese, R., Salvi, S., Sood, P., Karsiya, J., & Kumar, D. (2022). Carbon nanotubes in COVID-19: A critical review and prospects. Colloid and Interface Science Communications, 46, 100544. Vecitis, C. D., Zodrow, K. R., Kang, S., & Elimelech, M. (2010). Electronic-structure-dependent bacterial cytotoxicity of single-walled carbon nanotubes. ACS Nano, 4(9), 5471–5479. https:// doi.org/10.1021/NN101558X Vecitis, C.  D., Schnoor, M.  H., Rahaman, M.  S., Schiffman, J.  D., & Elimelech, M. (2011). Electrochemical multiwalled carbon nanotube filter for viral and bacterial removal and inactivation. Environmental Science & Technology, 45(8), 3672–3679. Vidic, J., Manzano, M., Chang, C. M., & Jaffrezic-Renault, N. (2017). Advanced biosensors for detection of pathogens related to livestock and poultry. Veterinary Research, 48(1), 1–22. Wang, Y. X., Ye, Z. Z., Si, C. Y., & Ying, Y. B. (2012). Application of Aptamer based biosensors for detection of pathogenic microorganisms. Chinese Journal of Analytical Chemistry, 40(4), 634–642. https://doi.org/10.1016/S1872-­2040(11)60542-­2 Wang, X., Jiao, C., Wang, T., & Yu, Z. (2016). Study on DNA damage induced by the reactive oxygen species generated in situ based on the multi-walled carbon nanotubes and hemoglobin. Journal of Electroanalytical Chemistry, 767, 182–187. https://doi.org/10.1016/J. JELECHEM.2016.02.030

Carbon Nanotubes for Antimicrobial and Antiviral Applications: Immunological…

365

Wang, X.-D., Vinodgopal, K., Dai, G.-P., Wang, X.-D., Vinodgopal, K., & Dai, G.-P. (2019). Synthesis of carbon nanotubes by catalytic chemical vapor deposition. Perspective of Carbon Nanotubes. https://doi.org/10.5772/INTECHOPEN.86995 Wang, M., Wang, C., Chen, M., Luo, M., Chen, Q., & Lei, B. (2022). Mechanics-electro-adaptive multifunctional bioactive nanocomposites hydrogel for inducing spinal cord regeneration. Chemical Engineering Journal, 439, 135629. https://doi.org/10.1016/J.CEJ.2022.135629 Wasik, D., Mulchandani, A., & Yates, M. V. (2017). A heparin-functionalized carbon nanotube-­ based affinity biosensor for dengue virus. Biosensors and Bioelectronics, 91, 811–816. Watt, M. R., & Gerhardt, R. A. (2020). Factors that affect network formation in carbon nanotube composites and their resultant electrical properties. Journal Of Composites Science, 4(3), 100. https://doi.org/10.3390/JCS4030100 Weiss, S. R., & Navas-Martin, S. (2005). Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiology and Molecular Biology Reviews, 69(4), 635–664. WHO. (2017). Global action plan on antimicrobial resistance. World Health Organization, 10(9), 1–28. www.paprika-­annecy.com WHO. (2023). WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. https://covid19.who.int/ Wiser, M. F. (2022). Protozoa. Reference Module in Life Sciences. https://doi.org/10.1016/B9780-­12-­822562-­2.00064-­5 Xing, S., Yan, M., Yang, Y., Wang, Y., Hu, X., Ma, B., & Kang, X. (2023). Diacerein loaded poly (styrene sulfonate) and carbon nanotubes injectable hydrogel: An effective therapy for spinal cord injury regeneration. Journal of Cluster Science, 34(1), 565–576. https://doi.org/10.1007/ S10876-­022-­02240-­7 Yadav, D., & Sanserwal, M. (2022). A comprehensive review of the effects of various factors on the thermal conductivity and rheological characteristics of CNT nanofluids. Journal of Thermal Analysis and Calorimetry, 148(5), 1723–1763. https://doi.org/10.1007/S10973-­022-­11821-­7 Yagublu, V., Karimova, A., Hajibabazadeh, J., Reissfelder, C., Muradov, M., Bellucci, S., & Allahverdiyev, A. (2022). Overview of physicochemical properties of nanoparticles as drug carriers for targeted cancer therapy. Journal of Functional Biomaterials, 13(4), 196. https:// doi.org/10.3390/JFB13040196 Yang, J. (2020). Inhibition of SARS-CoV-2 replication by acidizing and RNA lyase-modified carbon nanotubes combined with photodynamic thermal effect. Journal of Exploratory Research in Pharmacology, 5(2), 18–23. Yang, N., Chen, X., Ren, T., Zhang, P., & Yang, D. (2015). Carbon nanotube based biosensors. Sensors and Actuators B: Chemical, 207, 690–715. Yola, M. L., & Atar, N. (2021). Novel voltammetric tumor necrosis factor-alpha (TNF-α) immunosensor based on gold nanoparticles involved in thiol-functionalized multi-walled carbon nanotubes and bimetallic Ni/Cu-MOFs. Analytical and Bioanalytical Chemistry, 413(9), 2481–2492. https://doi.org/10.1007/S00216-­021-­03203-­Z Yu, H., Guan, F., Miller, H., Lei, J., & Liu, C. (2023). The role of SARS-CoV-2 nucleocapsid protein in antiviral immunity and vaccine development. Emerging Microbes & Infections, (just-­ accepted), 2164219. Zhang, F., Wang, Z., Vijver, M. G., & Peijnenburg, W. J. (2021). Probing nano-QSAR to assess the interactions between carbon nanoparticles and a SARS-CoV-2 RNA fragment. Ecotoxicology and Environmental Safety, 219, 112357. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., et al. (2020a). A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine, 382, 727–733. Zhu, Y., Xu, J., Wang, Y., Chen, C., Gu, H., Chai, Y., & Wang, Y. (2020b). Silver nanoparticles-­ decorated and mesoporous silica coated single-walled carbon nanotubes with an enhanced antibacterial activity for killing drug-resistant bacteria. Nano Research, 13(2), 389–400. https:// doi.org/10.1007/S12274-­020-­2621-­3

Carbon Quantum Dots for Medical Applications Chelladurai Karthikeyan Balavigneswaran and Vignesh Muthuvijayan

Overview The increase of human population has contributed to the surge of pollution and contamination of air, soil, and water. This resulted in a wide spread of pathogens such as bacteria, fungi, viruses, or parasites and infectious diseases. Nearly one-­third of annual global deaths is caused by infectious diseases. Antimicrobial agents are the primary medicines for the treatment of infectious diseases especially caused by bacteria and viruses. Further, many pathogens have evolved and resulted in multidrug resistance (MDR) against antibiotics such as fluoroquinolones, chloramphenicol, trimethoprim, various carbapenem, and β-lactam, due to their extensive usage during the last few decades (Organization, 2014). It is also reported that the number of deaths caused by antimicrobial-resistant infections is nearly 700,000 per year. The mechanism of resistance to antimicrobial agents could be due to inactivation/modification, alteration/change in the target site, and decreasing permeability/efflux of the antibiotics. This resistance mechanism may vary from species to species (Abushaheen et al., 2020). For example, Gram-negative bacteria such as Escherichia coli (E. coli) change the nature of their cell wall to restrict the entry of antibiotics (Miller, 2016). Grampositive bacteria, such as Klebsiella pneumoniae and Staphylococcus aureus, produce some enzymes that modify the drug molecule and thus it loses its activity (Santajit & Indrawattana, 2016). These MDR microbes cause sepsis, which increases the mortality rate. If no practical actions are taken to diminish the antimicrobial-resistance by 2050, every year, approximately ten million people will be affected (Li et al., 2022a, b). C. K. Balavigneswaran (*) · V. Muthuvijayan (*) Department of Biotechnology, Tissue Engineering and Biomaterials Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 V. Kokkarachedu, R. Sadiku (eds.), Nanoparticles in Modern Antimicrobial and Antiviral Applications, Nanotechnology in the Life Sciences, https://doi.org/10.1007/978-3-031-50093-0_16

367

368

C. K. Balavigneswaran and V. Muthuvijayan

The drug resistance of pathogenic microbes is a threat to the healthy survival of human beings. The new antibiotics being developed are derived from the existing chemical structure of antibiotics, which also increases the drug-resistance in the due course of time (Crofts et al., 2017). Therefore, unremitting efforts have been made to develop new antimicrobial agents. Nanomaterials do not easily develop drug resistance due to (1) high membrane permeability and (2) efflux pump inhibition effect. Several nanomaterials such as metals (Ag and Au) and metal oxides (CuO, Fe2O3, and ZnO) have shown effective antibacterial activity against many pathogens (Raghunath & Perumal, 2017). However, the release of metal ions produces some cytotoxic effects. Recently, less toxic carbon-based nanomaterials have been identified as potential antimicrobial agents. The environment friendly carbon materials are generally used in daily life, and they have shown minimal toxicity (Anand et al., 2019). Graphene-based nanomaterials have shown potent antimicrobial properties, but they can also affect the mitochondrial activity of cells (Seabra et al., 2014). Carbon nanomaterials are a class of low-dimensional spherical luminescent materials with a size of ~10 nm that have great interest in medical sciences research, such as drug delivery, bioimaging, photothermal therapy, gene delivery, and cell-­ based tissue engineering in the past three decades. Figure 1 shows different forms

Fig. 1  Various carbon nanomaterials, including fullerene, carbon nanotube, graphene, carbon dot, and nanodiamond. (Reproduced with permission (Hong et al., 2015))

Carbon Quantum Dots for Medical Applications

369

of carbon nanomaterials. Carbon nanomaterials are mainly composed of sp2 carbon atoms, forming a seamless network of conjugated π- electrons. However, the carbon dots (CDs) are hybridized with mixed sp2 and sp3 carbon atoms plus defects and heteroatoms (Hong et al., 2015). The CDs can be functionalized easily due to the available surface functional groups. CDs are classified into carbon nanodots (CNDs), carbon quantum dots (CQDs), graphene quantum dots (GQDs), and carbonized polymer dots (CPDs) according to their different structures. The physicochemical properties of CDs can be tailored by the synthetic precursor, purification method, and surface functionalization; thereby, the antimicrobial property of CDs can be modulated. Owing to their potential applications in medical sciences, the peculiar properties of CDs have been extensively studied. In this book chapter, we summarize the method of preparation, structural characteristics of CDs to be an antimicrobial agent, and the mechanism of its antimicrobial effect.

Factors Affecting the Properties of CDs The CDs have comprehensive properties such as conductivity, catalytic activity, various levels of interaction with biomolecules, and antimicrobial activity. All these properties depend on their morphological, physical, and chemical properties, including lateral size, purity, structural defects, charge, functional groups, degree of oxidation, and hydrophilicity. We can control the size, morphology, and other properties of CDs via the mode of synthesis (Liu et al., 2020).

Synthesis of Carbon Dots Traditionally, the CDs can be synthesized using “top-down” and “bottom-up” approaches. In the top-down approach, the destruction or dispersion of carbonaceous macromolecules such as graphite, nano-diamonds, carbon nanotubes, and activated carbon into nano-sized CDs is performed by physical, chemical, or electrochemical methods. On the other hand, bottom-up synthesis of CDs involves polymerization, followed by carbonization of small organic precursors such as citric acid, glucose, and sucrose. The top-down approaches typically require an additional step for surface functionalization/passivation, but “bottom-up” approaches do not require the additional step and the surface passivation can be accomplished in a one-­ pot synthesis. Extensive details on various methods of synthesis of CDs have been published elsewhere (Choi et al., 2018; Wu et al., 2017).

370

C. K. Balavigneswaran and V. Muthuvijayan

Top-Down Approach Laser Ablation Laser ablation is generally used to prepare various nanostructures with controlled size and morphology. The high energy laser pulse is passed to the target carbon molecules to irradiate the surface and to create high temperature and pressure. This high temperature rapidly evaporates the target molecules and transfers them into a plasma state where they crystallize to form nanostructures (Wu et al., 2017; Zeng et al., 2012). Chemical Oxidation Chemical oxidation is a process in which the oxidation of small organic molecules are carbonized to nano-carbonaceous materials using oxidative reagents such as HNO3 and H2SO4. This is a simple and cost-effective technique as it does not require any high-end equipment. The oxidative process is advantageous to introduce functional groups such as –OH and –COOH as well as the functionality modulate the hydrophilicity and emission property of the CDs. However, harsh conditions and drastic processes are the major drawbacks of this procedure (Wu et al., 2017). Electrochemical Carbonization Electrochemical carbonization is a simple technique for synthesizing CDs at normal temperature and pressure conditions. The synthesis of controlled size of CDs can be achieved by adjusting the applied electrode potentials (Bao et al., 2011). Ultrasonic Synthesis Ultrasonic sound is known to generate different pressure in the liquid to form and destruct small vacuum bubbles. The cavity produced in these bubbles can speed-up the hydrodynamic shear forces, liquid jets, and de-agglomeration. These ultrasonic waves can break down large carbon materials into smaller CDs (Lin et al., 2018). Bottom-Up Approach Hydrothermal Synthesis Hydrothermal method is a direct, efficient, economical, easy to handle, and impregnable route to synthesize CDs from diverse carbon-based precursors through polymerization and carbonization reactions. In a hydrothermal method, carbon precursor

Carbon Quantum Dots for Medical Applications

371

(small molecule like citric acid) is dissolved in an appropriate solvent and the reaction was performed at a high temperature (100–200 °C) in the absence of air in a Teflon-lined autoclave. The small organic moieties join together to form carbogenic cores and then grow into CDs ranging from 2 to 10 nm in size. It has been widely used due to the high reactivity of the reactants, easy control of the solution, little harm to the environment, and low energy consumption under hydrothermal conditions (Anwar et al., 2019). Microwave-Assisted Heating Method The microwave-assisted method is an alternative method to the hydrothermal technique, where microwave is utilized as a source of heat. It is employed to break down the chemical bonds present in the substrate and synthesis of CDs. This technique achieves a localized heating and efficient synthesis of CDs due to the strong interaction of microwaves with the carbon-sourced material. Also, it reduces the reaction time and produces a uniform size of CDs (Anwar et al., 2019).

Biocompatibility and Toxicity of Carbon Dots The application of CDs in biomedical science is broad; thus, the possible interactions between CDs and biological systems must be studied. The in vitro toxicity of the CDs could be evaluated using studies such as cell proliferation, apoptosis, necrosis, oxidative stress, and DNA damage. The in vivo evaluation includes absorption, distribution, interaction, metabolism, retention, and excretion in a living organism. In general, the toxicity of material arises due to its chemical nature. Especially in the case of CDs, the toxicity could be due to the type of functionalization. The CDs showed no toxicity even in the range of hundreds of μg mL−1, which is at least 10 times higher than the semiconductor quantum dots used for biological applications. Further, the polymer functionalized CDs showed less or similar toxicity compared to the pristine polymer (PEI, PEG, etc.) (Belza et al., 2021). In addition, the CDs have been shown to modify the gene-specific DNA methylation in some studies, which also decreased the viability of cells. The charge of the nanoparticles also influenced the viability of cells, where the positively charged and negatively charged CDs showed 90% viability with concentration of 100 and 500 μg mL−1, respectively (Sima et al., 2020). The in vivo evaluation of CDs is also important. Tao et al. have reported the toxicity of CDs in the mice model. They found that the fluorescent CDs did not show any significant side effects, and they were excreted from the body in urine (Tao et al., 2012). Further, Dong et al. studied the activity of CDs in mice. They found that the CDs decreased apoptotic proteins in the brain and liver, confirming that the synthesized CDs ameliorate D-galactose induced aging. The authors concluded that the biocompatible CDs, which inhibit the oxidative stress, could be used for

372

C. K. Balavigneswaran and V. Muthuvijayan

anti-­aging. In another study, Chung et al. reported compatibility of the citrate functionalized CDs in zebrafish. They observed that the CDs showed low toxicity and were eliminated rapidly from the embryo and eleutheroembryo of the zebrafish (Chung et al., 2021). Although there have been many reports suggesting the biocompatibility of CDs, there is still a lack of clinical trial evidence of CDs. Moreover, the regulatory status related to carbon nanomaterials and their commercial use are still under discussion and yet to be addressed by legislative bodies (Belza et al., 2021).

Mode of Administration CDs have been extensively used for antibacterial and antiviral applications due to their low toxicity and efficient antimicrobial activity (Serrano-Aroca et al., 2021). The CDs administration into the living system is ideally an exogenous molecules and administered into the human body via parenteral or enteral routes. The administration of CDs via intravenous mode is preferred since in this mode, they rapidly distribute throughout the entire body and increases the efficiency of CDs. During the circulation in the bloodstream, CDs will be taken by the target cells or excreted. The movement of the CDs into the targeted site is achieved by the continuous endothelium. After leaving the circulatory system by crossing the vascular endothelium, the CDs can interact with target tissues. The cellular uptake of CDs is dependent on particle size, charge, and hydrophobicity/hydrophilicity. It has been reported that the passive cut-off size of nanomaterials for tight junctions (blood-brain barrier, spinal cord, and retina) and adherent junctions (skin, muscle, heart, lung, and adipose tissue) are