Tackling COVID‐19 Using Antiviral Nanocoating's—Recent Progress and Future Challenges

Abstract

In the current situation of the global coronavirus disease 2019 (COVID‐19) pandemic, there is a worldwide demand for the protection of regular handling surfaces from viral transmission to restrict the spread of COVID‐19 infection. To tackle this challenge, researchers and scientists are continuously working on novel antiviral nanocoatings to make various substrates capable of arresting the spread of such pathogens. These nanocoatings systems include metal/metal oxide nanoparticles, electrospun antiviral polymer nanofibers, antiviral polymer nanoparticles, graphene family nanomaterials, and etched nanostructures. The antiviral mechanism of these systems involves depletion of the spike glycoprotein that anchors to surfaces by the nanocoating and makes the spike glycoprotein and viral nucleotides inactive; however, the nature of the interaction between the spike proteins and virus depends on the type of nanostructure and a surface charge over the coating surface. In this article, the current scenario of COVID‐19 and how it can be tackled using antiviral nanocoatings from the further transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), along with their different mode of action, are discussed. Additionally, it is also highlighted different types of nanocoatings developed for various substrates to encounter transmission of SARS‐CoV‐2, future research areas along with the current challenges related to it, and how these challenges can be resolved.

In this review, the current scenario of COVID 19 and how it can be tackled using antiviral nanocoatings has been discussed. Additionally, different types of nanocoatings developed for various substrates to encounter transmission of the SARS‐CoV‐2, future research areas along with the current challenges, and how these challenges can be resolved is also highlighted.

1. Introduction

Virus infections are one of the primary reasons of sickness and mortality around the world, as well as one of the main reasons of major economic loss. Till now the conventional treatment of such type of viral infections include therapeutics and vaccination based upon targeting key processes in the various stages of virus life cycle. However, most of the viruses change their characteristics with time due to mutation in their genes which make them drug resistant, which necessitates additional resources for the development of new drugs. In this regard, in the month of December 2019, a new RNA virus from the group of coronavirus was reported, which causes pneumonia and fever, was discovered in China.^{[ 1 ]} After few times on February 11, 2020 the Coronavirus Study Group (CGS) of the International Committee on Virus Taxonomy (ICTV) entitled the virus as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) based on phylogeny and taxonomy.^{[ 2 ]} On that same day World Health Organization (WHO) specified the disease caused by SARS‐CoV‐2 is “coronavirus disease 2019” (COVID‐19).^{[ 3 ]} Subsequently one month later on March 11, 2020 WHO declared the COVID‐19 outbreak as a pandemic. As of now in May 2022, SARS‐CoV‐2 has spread throughout the globe in over 222 countries, along with over 300 million of infections and over hundred thousand of deaths.^{[ 4 ]}

Since the outbreak of COVID‐19 in mid‐2020, there is a worldwide demand for smart diagnosis, effective treatment, as well as mitigation of the spread of infection. To encounter the spread of SARS‐CoV‐2 the traditional sensitization process is not that much effective due to their periodical application over small period of time, moderate to high cost of production to application process. In this regard, nanotechnology can deliver a number of strategies to fight with viruses, from both outside as well as inside of the host, and there are already several nanotechnology‐based platforms have been successfully implemented in preclinical studies to confront human viral pathogens such as human immunodeficiency virus (HIV), herpes simplex, and respiratory viruses. For example, a) nanomaterials can act as a smart carrier for direct delivery of novel antiviral drugs to support the targeted therapies, b) nanomaterials can detect infection in a very rapid, sensitive, and specific way, c) nanomaterials‐based face masks and filters which can prevent spread of viruses through air/water and last but not the least d) nanomaterials‐based antiviral coatings which are resistant to viral adhesion and can kill/inactivate the virus.

Although extensive research has been performed to explore the efficacy of nanotechnology‐based solutions that prevent bacterial transmission by killing or reducing attachment of bacteria on surface, whereas there are limited number of studies, which are focused on viral transmission. The crisis of COVID‐19 re‐emphasized the importance of nanotechnology to tackle the transmission of SARS‐CoV‐2. In this regard, it has been observed, that survival of active viruses on surfaces differs significantly based on the type of the virus and the surfaces where they are sitting on. For example, in case of coronavirus the viability on different surfaces varies in between 2 to 216 h.^{[ 5 ]} In the absence of host cells, instantaneous deactivation of some viruses on surfaces (e.g., Rinderpest virus),^{[ 6 ]} and disability of some viruses to spread outside the host body (e.g., HIV)^{[ 7 ]} have restricted the attention to the transmission of viruses through surfaces. However, viruses like SARS‐CoV‐2, which can remain active for a prolonged period of time on surfaces, possess a great risk of transmission via surfaces which demands the urgent need for cost effective solutions that prevent the survival of viruses on surfaces.

In this review article, the current scenario of COVID‐19 and how it can be tackled using antiviral nanocoating from further transmission of its virus along with their different mode of actions are discussed. Additionally, the author also highlights different type of nanocoatings developed for various substrates to encounter transmission of SARS‐CoV‐2, future research areas along with the current challenges related to it, and how these challenges can be resolved.

2. Structure of Viruses, Interaction between Host and Virus and Their Transmission

Viruses are small in size, typically in the range of 10–200 nm, and cause infectious disease. Structurally viruses are much smaller compared to a normal bacterium and can be observed in an electron microscope. One of the exclusive behavior of viruses is that, they are dependent on “host cells” of other living organism to reproduce; without “host cells” they cannot replicate on their own and remain inactive. Virus consists a single or double stranded nucleic acid (RNA/DNA) enclosed by a protein shell known as a capsid; capsid protects the inner genetic material from outside.^{[ 8 ]} The structure of a typical virus is shown in Figure 1a. In case of coronavirus, which causes COVID‐19, the capsid made of lipid and can be destroyed by soap like material. The diameter of coronavirus generally lies in between 60 to 140 nm and its capsid contains spike‐type structures forming an appearance similar to crown under electron microscope.^{[ 9 ]}

Figure 1.

Structure of virus and mechanistic action. a) Structure of a coronavirus. b) Surface addition of viruses via electrostatic interaction. c) The schematic diagram of the mechanism of SARS‐CoV‐2 entry, viral replication, and viral RNA packing in the cell. Reproduced with permission.^{[ 11 ]} Copyright 2021, MDPI.

Virus can spread in various ways such as aerosols produced during coughing, sneezing in air or by vectors like flies, mosquitoes, and by the transmission of body fluids such as blood, saliva, and semen.^{[ 10 ]} When a virus enters into host cells, it starts to duplicate and reproduce its virion rapidly. As a consequence, our body activate its natural immune system and produce antibodies that will bind with the viruses and make them incapable of replicating within the body. The viral replication mechanism within a host cell is shown in Figure 1c. Among several types of viruses, some of the viruses such as HIV, Human papillomavirus (HPV) are less susceptible to our natural immune system and causes life threatening diseases. As stated in above, COVID‐19 is also an extremely infectious disease caused by novel coronavirus SARS‐CoV‐2 (a virus from of coronavirus) and leads to respiratory infections. The symptoms of COVID‐19 include cough, cold, fever, headache, tiredness, loss of taste and smell, chest pain, difficulty in breathing, etc.

The main mechanism for transmission of viruses through surfaces is adsorption, and this adsorption can be of two types: physical adsorption and electrostatic adsorption. A schematic diagram of electrostatic adsorption of virus on a surface is shown in Figure 1b. It has been identified that the number of viruses adsorbed on any surface is the linear function of the square root of time. Thus, the more time it stays on the surface there is more chance that it strongly bound to surface and subsequently there is more opportunity to affect the population. In this regard, there are few strategies to minimize the transmission of viruses from surfaces such as by reducing the time of interaction of virus with a material or by introducing materials with surface properties which are not sustainable for viruses.

3. The Antiviral Action of Nanomaterials against Corona Virus Models

Since the outbreak of coronavirus in 2020 several studies have been conducted worldwide to find the antiviral action of nanomaterials against SARS‐CoV‐1, MERS‐CoV, and other corona virus models. Among several types of nanomaterials silver nanoparticles (AgNPs),^{[ 12 ]} nano copper oxide (nano CuO),^{[ 13 ]} nano titanium oxide (nano TiO₂),^{[ 14 ]} nano zinc oxide (nano ZnO),^{[ 15 ]} graphene oxide (GO)^{[ 16 ]} have been demonstrated good antiviral activity against coronavirus. For example, Chen and co‐workers examined the pathways of antiviral action induced by silver nanoparticles and nanowires against Transmissible gastroenteritis virus (TGEV), which is a typical variant of coronavirus.^{[ 17 ]} They observed that, both silver nanoparticles and nanowires established direct interaction with glycoprotein present on capsid of coronavirus, which restricted the initiation of further reproduction of virus. Further in‐depth study revealed that silver nanoparticles induced TGEV‐mediated apoptotic signals cascades which inhibit further growth of virus. In case of nano CuO it was observed that with time nano CuO releases copper ions which ultimately leads to generation of reactive oxygen species (ROS) and neutralizing the viruses.^{[ 18 ]} Although it has been also observed that other than nano CuO, AgNPs, and nano ZnO also kill virus system via ROS mediated pathways. However, one major problem related to these nanoparticles is their cytotoxicity; to reduce the cytotoxicity, researchers are currently focused on biomimetic synthesis of these nanoparticles without compromising their antiviral property. For instance, Wu and co‐workers reported a multifunctional nanocoating based on anti‐pathogen micelles tethered with copper nanoparticles via a biomimetic synthesis method using l‐vitamin C.^{[ 19 ]} The multifunctional nanocoating served three different purposes at once including antiadhesion of pathogens on surface, ion released killing, as well as contact killing of pathogens. In case of nano TiO₂ the sterilizing effect comes from its inherent photocatalytic activity. In the presence of UV rays, TiO₂ produces strong oxidative effect, which is exploited as photocatalytic disinfectant to design antiviral nanocoatings. The detailed antiviral actions of these nanoparticles discussed in below sections.

Other than metal and metal oxide based systems recently other nonmetal nanomaterials also getting attention as an antiviral agent due to their low cytotoxicity profile and easy bioavailability.^{[ 20 ]} For example, turmeric a traditional natural herb well‐acknowledged for antipathogenic activity; turmeric possesses curcumin a phenolic compound which is the main reason behind its antipathogenic activity.^{[ 21 ]} Curcumin's phenolic hydroxyl groups play a critical role in its anti‐oxidant, anti‐inflammatory, and radical scavenging properties. It is already reported that curcumin have the ability to obstruct virus such as hepatitis c, influenza, and HIV.^{[ 22 ]} In addition to that, a recent study suggested that curcumin possesses good antiviral activity against SARS‐CoV‐1 in the dosage of 3–10 µm.^{[ 20 ]} However, insolubility of curcumin in water restricts its processability and clinical application. To overcome this challenge researchers are now coming up with nanoscale curcumin which could be a solution to low aqueous solubility and poor bioavailability of natural curcumin.^{[ 23 ]} For instance, carbon dots (CDs) synthesized from curcumin is a promising way to improve the bioavailability of curcumin. In such an attempt, Han and co‐workers reported synthesis of cationic CDs from curcumin via hydrothermal route and studied their antiviral inhibition efficacy against porcine epidemic diarrhea virus (PEDV) as a coronavirus model.^{[ 24 ]} The cationic CDs is restricted the proliferation of PEDV by destroying the structure of surface protein in viruses, thereby inhibiting viral entry. In addition to that, the curcumin derived CDs (CCM‐CDs) suppresses the synthesis of negative‐strand RNA of the virus, the budding of the virus, and the accumulation of ROS by PEDV. Furthermore, it was also identified that CCM‐CDs also restrict viral replication by controlling the production of interferon‐stimulating genes (ISGs) and proinflammatory cytokines. Other than CDs, graphene nanomaterials are also another promising carbon family nanomaterial which gain widespread popularity in biomedical field due to its antipathogenic property. It is already well‐recognized for their antibacterial properties but after the outbreak of COVID‐19, their antiviral properties are also exploited by researchers. For instance, in a recent study Gu et al. reported that molecular engineered graphene can be used for broad spectrum antiviral applications.^{[ 25 ]}

In addition to intrinsic antiviral property of nanomaterials, the specially designed nano surfaces own super hydrophobicity and superoleophobicity, which can prevent the adherence of viruses to this type of specially designed surfaces. It is already reported that, compared to bare surfaces, superhydrophobic surfaces show a 99.99995 percent reduction in SARS‐CoV‐2 adhesion.^{[ 26 ]}

4. Different Metal and Non‐Metal Based Antiviral Nanomaterials

4.1. Silver

Silver is a well‐acknowledged antimicrobial material from very past and in recent days it is much popular in nanoform due to its superior antiviral properties compared to its bulk form.^{[ 27 ]} Silver neutralizes virus systems by interacting with viral envelope and surface proteins and subsequently blocks viral penetration into cells, restricting cellular pathways, communication with the viral genome, and interaction with viral replication factors. In this regard a significant amount of research has been conducted on mechanism of antiviral property of silver in various form like ions, nanoparticles and hybrid coatings to develop effective antiviral surfaces.

For example, in a work by Lara et al. tried to find the mode of antiviral action silver nanoparticles (AgNPs) against HIV‐1.^{[ 28 ]} Where they observed that, AgNPs exert antiviral activity in an early stage of viral replication, most probably as a virucidal agent or as an inhibitor of viral entry. In particular they identified that, AgNPs bind with gp120 in a way that it prevents CD4‐dependent virion binding, fusion, and infectivity, acting as an effective virucidal agent against cell‐free virus and cell‐associated virus. Additionally, AgNPs also demonstrated inhibition at post entry stages of viral replication for which the mechanism was not yet established. It was perceived that; silver has an affinity toward phosphate and sulfur groups which can destroy cell membrane due to the binding with phospholipid tails and proteins containing cysteine or methionine. Furthermore, Ag⁺ ions generate ROS within cells, which is also another reason of antibacterial and antiviral activity of silver nanoparticles. More specifically in case of antiviral action of AgNPs, AgNPs are supposed to restrict the accessibility of the virus to cells by binding of envelope proteins, as for example glycoprotein gp120, which inhibits CD4‐dependent virion binding and infectivity.^{[ 28 ]}

One of the common approaches to make antiviral coating is to incorporate silver ions into a system. For example, a study by Weber and co‐workers reported a sol‐gel coating system composed of silver as well as copper and zinc.^{[ 29 ]} Antiviral assays using HIV‐1, dengue virus, herpes simplex virus (HSV), influenza virus, and coxsackie virus revealed that the coating system is highly effective for both double‐stranded DNA virus and positive sense single‐stranded RNA virus. Significant log scale reductions were noticed for this type of viruses except influenza and coxsackievirus, this may be due to the nature of these viruses as they are negative‐sense RNA‐based and non‐enveloped, respectively. Which suggests the hybrid coating has potential to provide antiviral protection on surfaces and materials in healthcare industry.

Castro‐Mayorga et al. also evaluated the efficacy of AgNO₃ as well as AgNPs in reducing recovered titer levels of norovirus surrogates in a time span of 5 months.^{[ 30 ]} Both silver ions and AgNPs significantly decreased the norovirus infectivity in a dose‐dependent manner within the range of 2.1 and 21 mg L⁻¹. More noticeably AgNPs activity as an antiviral agent preserved constant up to 150 days if the AgNPs concentration was more than 2.1 mg L⁻¹. However, in case of silver nitrate it was most effective up to first 75 days, due to the reduction and aggregation of ions with time. Furthermore, they prepared poly (3‐hydroxybutyrate‐co‐3‐hydroxyvalerate) (PHBV) films by depositing a coating of thermally post‐processed electrospun PHBV/AgNPs fiber mats over compression molded PHBV films. After 1day exposure at 37°C and 100% relative humidity, no infectious feline calicivirus were recovered when in contact with the AgNPs films while murine norovirus titers reduced by 0.86 log. Based on these results they predicted that, the silver ions released from the immobilized AgNPs are accountable for the viral deactivation, however more detailed investigation still required to establish the study.

In a recent study Bogdanchikova and co‐workers investigated the efficacy of SARS‐CoV‐2 infection in health workers.^{[ 31 ]} In this study, at first they studied the in vitro inhibitory efficacy of AgNPs against SARS‐CoV‐2, where they observed that, AgNPs did not totally eliminate viral reproduction, however up to 80% reduction in virus concentration can be achieved with a 0.03% AgNPs concentration. Inspired from this promising result, they assessed the effects of mouthwash and nose rinse with ARGOVIT silver nanoparticles (AgNPs), for the prevention of SARS‐CoV‐2 contagion in health workers consider as high‐risk group of acquiring the infection in the General Tijuana Hospital, Mexico, which is exclusively for the patients diagnosed with COVID‐19. A random experiment was performed by them, where a total 231 candidates participated in this study over a time frame of 9 weeks. The “experimental” group used AgNPs solution to rinse mouth and nose whereas the “control” group rinsed the mouth and nose in a conventional way. It was noticed that, the occurrence of SARS‐CoV‐2 infection was significantly low in case of “experimental” group (two participants of 114, 1.8%) compared to the “control” group (thirty‐three participants of 117, 28.2%), with an 84.8% efficiency; which confirms AgNPs helps in the inhibition of SARS‐CoV‐2 infection in health personnel who are exposed to patients diagnosed with COVID‐19 and can be used in coating system to minimize the transmission of SARS‐CoV‐2 infection. Ryo and his team members also evaluated potent antiviral activity of polyvinylpyrrolidone (PVP) coated AgNPs on SARS‐CoV‐2.^{[ 32 ]} Briefly they have used a plethora of AgNPs of different sizes and concentration and noticed that particles of diameter around 10 nm were effective in preventing extracellular SARS‐CoV‐2 at concentrations of 1–10 ppm while cytotoxic effect was found at concentrations of 20 ppm and above. Furthermore, Luciferase assay revealed that AgNPs potently prevented viral entry via disrupting viral integrity as showed in Figure 2 . Which also support AgNPs efficacy against SARS‐CoV‐2.

Figure 2.

Characteristics of PVP coated 10 nm AgNPs in SARS‐CoV‐2 infection. Immunofluorescence imaging comparing the effect of 10 nm and 100 nm AgNPs against SARS‐CoV‐2 infection in VeroE6/TMPRSS2 cells. Cell nuclei (blue) and SARS‐CoV‐2 nucleocapsid protein in cytoplasm (red). A) NC—Negative control; PVP‐coated 10 nm AgNPs protect VeroE6/TMPRSS2 cells from SARS‐CoV‐2 infection mediated cell death. B) Crystal violet staining reveals partial protection with visible plaques (red arrowheads) and complete protection with absence of plaques (black arrowheads); Pseudovirus entry assay. C) PVP‐coated 10 nm AgNPs inhibit entry of pseudovirus in VeroE6/TMPRSS2 cells. NC—Negative control, nAb—neutralizing antibody. Reproduced with permission.^{[ 32 ]} Copyright 2020, Elsevier.

From commercial point of view AgNPs based antiviral nanocoating already launched by some of the leading giants in coatings industry like Akzonobel, Vitex, Nippon Paints. For example, AkzoNobel has launched new Dulux Wash & Wear Anti‐Viral paint in 2021 for Indian Market. The new range comes with improved variation of the Wash & Wear range that comes with the patented KidProof⁺ Technology, and an added layer of anti‐viral protection based on Silver Ion Technology.^{[ 33 ]} The Dulux Wash & Wear highly effective against human coronavirus NL‐63 (99% efficacy) with half an hour exposure on the painted surface; however they did not examined its efficacy against SARS‐CoV‐2. Vitex a company in Greece also launched an antiviral coating solution called VAIRO with silver ion technology.^{[ 34 ]} According to company's claim VAIRO's healthcare technology is based on composites in which encapsulated silver ions present in inorganic matrices and other booster components cause regulated release in wet as well as dry situations. Furthermore, upon application it delivers a modified hydrophilic slippery coating surface which proves inhospitable for virus and bacteria and enhance further antiviral‐antibacterial activity. They observed that, any walls painted with VAIRO offer great defense against Human Corona virus OC43, Human Corona virus HC 229E, Human Novel Corona virus SARS‐CoV‐2 (4 h contact can kill >99%), virus phage phi6, virus phage MS2 which are used as surrogates for many enveloped as well as not enveloped viruses, in numerous conditions. The VITEX with VAIRO antiviral solution is applicable to children's rooms, schools, nurseries medical practices, hospitals, maternity clinics, aged care facilities, restaurants, fitness centers as well as in shopping malls.^{[ 35 ]} Nippon Paints another leading giant in the paint industry also reported antiviral coatings with silver ion technology which can be applied in residential areas, health institutions and educational centers. They have launched three simultaneous products named Virusguard, Spotlessplus, Vinilex Fresh Plus. According to their claim all of these coating solutions are 99.9% effective against SARS‐CoV‐2, while Virusguard effective against HCOV‐229E, H1N1 and Coxsackievirus A16. In case of enveloped containing viruses, the silver ions present in these paints destroy the lipid membrane of viruses. When enveloped virus lands on walls painted by Virusguard, the silver ions present into it attract the virus and destroy the lipid membrane which ultimately make them non‐functional. Without lipid membrane, these viruses could not takeover a host to survive, and eventually causes the death of viruses. On the other hand, in case of non‐enveloped virus it destroys the protein coat, making them non‐functional.^{[ 36 ]}

Other than these giants some small companies also launched nanosilver based technology for prevention of the spread of SARS‐CoV‐2 (COVID‐19). For example, a small company from India, Harind Chemicals & Pharmaceuticals Pvt. Ltd. designed a cationic AgNPs based surface coating technology (NANOVA HYGIENE⁺) to combat the global pandemic.^{[ 37 ]} Briefly the NANOVA HYGIENE⁺ is an antipathogenic coating for surfaces such as plastics, metals and concretes that comprises the cocktails of non‐migratory quaternary ammonium cations and positively charged AgNPs as bioactive nanoparticles and dispersing this into binder polymers. They proposed that, the cationic silver inactivate the SARS‐CoV‐2 by interacting with its surface (spike) protein S based on its charge similar to HIV, Hepatitis viruses, etc.^{[ 38 ]} Additionally, the coatings system also possess good omniphobic properties as contact angles were greater than 130° and 50° when measured against water and hexadecane as probes, respectively.

4.2. Copper

Similar to AgNPs, copper nanoparticles also one of the well‐recognized antimicrobial metals till date and a lot of studies already done to examine the antimicrobial effect of copper. However antiviral actions of copper were new to the action and not that much explored yet. During antibacterial related investigations of copper, it has been found that several types of antibacterial mechanisms are involved with copper such as 1) permeabilization of plasma membrane, 2) peroxidation of cell membrane, 3) alteration of proteins, 4) inhibition of protein assembly and denaturation of nucleic acids, 5) ROS generation. In case of plasma membrane permeabilization copper ions produce electrostatic forces on the outer plasma membrane of cells, which causes membrane breakdown which ultimately leads to cell death. Alteration of proteins, inhibition of protein assembly and denaturation of nucleic acids takes place due to displacement of vital metals from their native‐binding sites of proteins or direct interactions of copper nanoparticles with the proteins/nucleic acids. Furthermore, cyclic redox reactions between Cu⁺ and Cu²⁺ generate highly reactive oxygen species (ROS) and these ROS eventually leads to cell death. Few studies reported that, copper targets the viral genome, specifically encoding genes which are crucial for viral infectivity. In this regard, it has been observed that the primary reason of inactivation for viruses such as murine norovirus are Cu(II) and Cu(I).^{[ 39 ]} In addition to that, contact killing mechanism another emerging approach for deactivation of pathogens due to their instantaneous action upon contact. For instance, Keevil and co‐workers discovered that planar copper possess significantly higher inactivation power toward influenza A virus compared to stainless steel, leaving just 500 infectious virus particles after 6 h from the 2 × 10⁶ virus particles, whereas stainless steel retained 500 000 infectious virus particles after 24 h.^{[ 40 ]} In another similar type of study, Sunada and co‐workers evaluated the efficacy of several solid‐state cuprous compounds, including cuprous oxide (Cu₂O), sulfide (Cu₂S), iodide (CuI), and chloride (CuCl) against influenza A virus against cupric sulfide (CuS), silver sulfide (Ag₂S) and bare silver (Ag). All of these cuprous compound's size differs in between 50–800 nm.^{[ 41 ]} Where they found that, cuprous compounds are far superior compared to solid‐state silver and cupric compounds against influenza A virus. They predicted three plausible mechanisms of antiviral activity of copper compounds including ROS generation, destabilization of virus envelope due to leached copper ions and direct contact killing. Bleichert et al. also used contact killing mechanism to make copper based antiviral surfaces, which can deactivate significant number of orthopoxviruses, monkeypox virus, and vaccinia virus within 3 min when exposed to copper surfaces.^{[ 42 ]}

Researchers have also examined inclusion of copper ions into other materials to introduce antiviral capabilities. For instance, in a pioneering work Karlstorm et al. investigated influence of Cu²⁺ along with Hg²⁺ in inhibition of protease, an essential protein for viral replication, from human immunodeficiency virus 1 (HIV‐1).^{[ 43 ]} They observed that, oxygen is not important for the deactivation of the protease, and that approximately stoichiometric concentrations of Cu²⁺ and Hg²⁺ions caused rapid and irreversible deactivation of protease. Due to such type of antiviral properties copper ions and particles are also used to prepare antiviral textiles, filters, and polymeric latex.^{[ 44} , ⁴⁵ , ⁴⁶ , ^{47 ]}

Early examples of this include, a work by Borkow and co‐workers where they made a polyester glove inseminated with copper to check its action against HIV‐1. Additionally, they prepared copper loaded polyester filter also to check its efficacy against HIV‐1 and West Nile virus (WNV).^{[ 44 ]} In this study, the antiviral effectiveness of copper loaded latex samples was evaluated based on the amount of copper incorporated in a dose‐dependent manner. Where an ≈5‐log reduction was identified for both of the viral infectious titers in presence of copper filter. In their subsequent work also, they have studied reduction of various viruses in suspension by copper oxide‐based filters. For their study they have selected a wide variety of viruses including rhinovirus‐2, yellow fever, influenza A, measles, respiratory syncytial, parainfluenza 3, Punta Toro, pichinde, HIV‐1, adenovirus type 1, cytomegalovirus and vaccinia virus.^{[ 45 ]} Where a maximum 2‐log reduction was observed in case of rhinovirus‐2, while decrease in reductions were identified with yellow fever, influenza A, measles, respiratory syncytial, parainfluenza 3, Punta Toro, pichinde, HIV‐1, adenovirus type 1, and cytomegalovirus, with vaccinia virus showing the minimal reduction of just 0.47‐log.^{[ 45 ]} Inspired from these exciting results of copper oxide based filters in 2010 the same research group designed a face mask loaded with copper oxide which resulted in the elimination of the human influenza A (99.85%) virus within half an hour, compared to recovered from control masks.^{[ 46 ]} A typical face mask loaded with copper oxide demonstrated in Figure 3a. The face masks consist of four different layers named as A, B, C, D, where layer A and D consist 2.2% w/w nano copper oxide particles along with a polypropylene layer (Figure 3b), interior layer B contains 2% nano copper oxide particles and polypropylene layer (Figure 3c) while layer C does not contain any copper oxide particles. Layer C contains only polyester.

Figure 3.

Copper based inorganic antiviral coatings. A,D) The test mask composed of 2 external spunbond polypropylene layers containing 2.2% copper oxide particles (weight/weight), B) one internal meltblown polypropylene layer containing a) 2% copper oxide particles (w/w) and one polyester layer containing no copper oxide particles; b) Scanning electronic microscope picture and X‐ray analysis of external layer A; c) Scanning electronic microscope picture and X‐ray photoelectron spectrum analysis of internal layer B. Reproduced with permission.^{[ 46 ]} Copyright 2010, PLoS.

It has been also reported that, cotton textiles containing Cu²⁺ held by zeolites can deactivate highly pathogenic H5N1 and comparatively low pathogenic H5N3 viruses even after short incubation time.^{[ 47 ]} It has been observed that, in presence of copper ion loaded textiles, H5N1 virus concentrations reduced by >5.0 log10 in MDCK cells within 30 min, whereas in case of H5N3 it was reduced by >5.0 log10 within 10 min. On the other hand, no decrease in the titers was observed on cotton textiles containing zeolites alone (Zeo‐textile). Li et al. also employed copper nanoparticles (CuNPs) as a part of layered system by combining the antimicrobial as well as antiviral properties of copper and chlorine dioxide (ClO₂).^{[ 19 ]} The multifunctional coating system offers “release‐killing,” “contact‐killing,” and “anti‐adhesion” properties. To prepare the coating system they have synthesized ClO₂ encapsulated polymeric nano micelles tethered with copper nanoparticles. The ClO₂ present in the micelles release over a time period of 15 days which allow long term release killing of virus; while the CuNPs deliver the contact killing. Testing of this coating system revealed that, a wide‐range of activity that killed a broad spectrum of pathogens including viruses (H1N1), bacteria, and spores. Plaque assay confirmed the complete deactivation of H1N1 virus within 1 min of the contact with the coating system as showed in Figure 4 . Furthermore, transmission electron microscopy images confirmed significant disruption in virus structure upon contact with this coating (showed in Figure 4A,B).

Figure 4.

Virucidal performance of the multi‐functional anti‐pathogen coating. A) Transmission electron microscopy (TEM) image of the H1N1 virus; B) TEM image of the H1N1 virus after contact with the coating; C) plaque assay image of an H1N1 infected host cell; D) plaque assay image of the coating inactivated N1N1 virus. Reproduced with permission.^{[ 19 ]} Copyright 2018, Royal Society of Chemistry.

In a recent work, published by Helfritch and co‐workers reported a kinetically deposited copper based antipathogenic surfaces.^{[ 48 ]} More specifically they examined spray coating methods with copper powder to check its antipathogenic effects. During their study they observed that, using a cold coating approach, with a coating velocity of 500–1000 m s⁻¹ and at a temperature of 150–400 °C (which is equivalent to many industrial application methods that exist to apply metal coatings) was most effective against influenza A, with 100% deactivation after just 10 min of contact to a 100 µL aliquot of virus. Associated to coronavirus, a primary antiviral study using copper on coronavirus done in 2015 by Warnes et al.^{[ 49 ]} Briefly they reported application of copper alloys for the deactivation of human coronavirus 229E and discovered that complete deactivation of 103 plaque‐forming units (PFU) in less than 60 min on a range of alloys. Specifically they noticed that, Cu/Zn brasses being very effective at 70% or higher copper concentrations.^{[ 49 ]} Furthermore it was also observed that, exposure of copper demolished the viral genomes and permanently affected virus morphology, including disintegration of envelope as well as dispersal of surface spikes. According to them, Cu(I) and Cu(II) were accountable for the deactivation of viruses, which was boosted by ROS generation on alloy surfaces, resulting in accelerated deactivation. In another very recent study, Palanisamy and co‐workers employed cold‐spray technique for rapid coating of copper on in‐use steel parts.^{[ 50 ]} Different still plates covered with cold spray copper showed in Figure 5 . Upon examining viricidal activity of copper coated samples they observed that, 96% of SARS‐CoV‐2 virus deactivated within 120 min which was significantly faster than the time required for stainless steel to deactivate the virus to the same level. Furthermore, it was discovered that the copper‐coated sample significantly reduces the lifetime of the SARS‐CoV‐2 virus to less than 300 min, which confirmed the ability of cold spray technology to produce copper coatings with virus‐killing properties in a short amount of time, allowing coated parts to be re‐deployed back into service. In another similar type of work, Shimizu and his team members assessed copper‐based nanoparticles (CuNPs) as a surface coating agent for antiviral properties against SARS‐CoV‐2.^{[ 51 ]} To synthesize the CuNPs (mainly composed of copper oxide), they have employed copper sulphate as a source of copper and subsequently prepared a CuNPs/resin‐based paint for spray coating of stainless steel. They observed that, SARS‐CoV‐2 lost 97.8% of its infectivity on the CuNPs/paint‐coated surface after 30 min and more than 99.995% after 60 min of exposure. The deactivation rate is 36 times faster than that on the paint alone‐coated and uncoated surfaces suggesting its potential antiviral coating applications.

Figure 5.

a) Macro‐photograph of an in‐use stainless steel push plate; b) copper coating on stainless steel push plate; c) polished copper coating; and d) copper‐coated push plate installed on a door. Reproduced with permission.^{[ 50 ]} Copyright 2020, Elsevier.

In another recent study, Chin and co‐workers exploited a transparent sprayable coatings based on polydopamine (PDA) and copper (Cu) (PDA/Cu) or cuprous oxide (Cu₂O) (PDA/Cu₂O) for deactivation of SARS‐CoV‐2.^{[ 52 ]} In their coatings system PDA act as an adhesive, that can be sprayed as well as it can polymerizes into a conformal film at room temperature. Their synthesized PDA/Cu coatings system deactivates 99.98% of SARS‐CoV‐2 within 1 h whereas PDA/Cu₂O system neutralizes 99.88% of SARS‐CoV‐2 within 1 h.

From commercial point of view, Corning from USA patented a glass‐ceramic technology, named Corning Guardiant based on copper.^{[ 53 ]} Under the certain test methods approved by US Environmental Protection Agency (EPA) paint and coatings containing Corning Guardiant able to kill more than 99.9% of SARS‐CoV‐2. According to Corning's claim, the antiviral activity of Corning Guardiant is highly durable with same level of antiviral efficacy even six years of scrubbing. Additionally Corning also collaborated with PPG and developed COPPER ARMOR an antiviral and antibacterial paint for interior surfaces which can neutralize SARS‐CoV‐2 along with outstanding antibacterial capabilities against Staph, Methicillin‐resistant Staphylococcus aureus (MRSA) and Escherichia Coli.^{[ 54 ]} The paint with copper technology inactivates viruses and bacteria on the painted surface within 2 h of exposure for up to 5 years. In India also, a team of scientists with an industry partner named Resil Chemicals situated at Bengaluru developed a self‐disinfecting CuNPs‐coated antiviral face mask to fight against the COVID‐19 pandemic.^{[ 55 ]} Currently Resil Chemicals producing such type of mask on industrial scale. The mask demonstrated high performance with 99.99% disinfection against the COVID‐19 virus as well as several other viral and bacterial infections, and is biodegradable, highly breathable, and washable.

4.3. Zinc

Zinc has also been well acknowledged for its antiviral property since the pioneering work by Korant et al. in early 1970 era, where they evaluated the efficacy of zinc against human rhinovirus (HRV).^{[ 56 ]} Their results indicated that 0.1 mm of zinc chloride solution is enough to reduce 99.99% of plaques formed for HRV. Additionally, they revealed that zinc can prevent proteolytic cleavage which restricts synthesis of viral polypeptides. It has been observed that, the mechanism for antiviral applications varies with viruses, as it does with most metals. In this regard, there are multiple mechanisms of viral deactivation including free virus deactivation, viral genome transcription, blockade in viral protein translation as well as inhibition of polyprotein processing. For instance, the effects of zinc on Herpes Simplex Virus‐I and II have been tested over a time span of four decades by researchers and their results suggested that, zinc can introduce antiviral functionality throughout the virus life cycle, including polymerase function, protein production and processing as well as free virus inactivation.^{[ 57 ]} It is worth mentioning that, several viruses depend on a zinc‐finger architecture for their duplication by host cells, which confirms the significance of zinc as an antiviral agent. A zinc finger is a small protein structural motif defined by the coordination of one or more zinc ions (Zn²⁺⁾ to stabilize the protein fold. In this regard, Forsyth and co‐workers discovered that, slight alterations in the nucleocapsid protein's zinc‐finger structure in HIV‐1 reduced the efficacy of chaperone action, which destabilizes nucleic acids during viral replication's reverse transcription process.^{[ 58 ]}

In case of antiviral applications of nano zinc, it is generally used directly in the form of zinc oxide (ZnO) or in a combination with other metals as an alloy. For example, Warnes and co‐workers exploited, the use of solid surfaces containing zinc as well as copper to produce an antiviral alloy.^{[ 59 ]} They revealed that, presence of zinc imparts synergistic effect along with copper and significantly neutralize human norovirus. Additionally, they found that a 1‐log reduction in murine norovirus infectivity when pure zinc was used, that suggest it can act as an antiviral agent on its own also.

Nano ZnO also emerged as a potent contender for antiviral coating applications due to its facile synthesis and good antiviral actions. For instance, Mishra et al. evaluated the use of micro‐nano filopodia like ZnO structures (shown in Figure 6a–e) for potential inhibitor against herpes simplex virus‐1 (HSV‐1).^{[ 15 ]} They proposed that, the filopodia like ZnO structures engage with virus and bind with heparan sulfate on the cell surface and restricts the virions outside human corneal fibroblast cells due to partially negatively charged oxygen vacancies on the ZnO micro/nanoscopic spikes. Preincubation of HSV‐1 with ZnO micro/nanospikes remarkably constrained the viral entry into cells. Furthermore, it was identified that, in presence of UV illumination, antiviral capability of ZnO micro/nanospikes tremendously enhanced due to formation additional oxygen vacancies. Examining the enzymatic activity of infected cells using optical density revealed that at a ZnO micro/nanospikes concentration of 100 µg mL⁻¹, less than 20% of HSV‐1 entered the cell, which increased to just under 30% entry at a ZnO micro/nanospikes concentration of 0.1 µg mL⁻¹ (without UV radiation), whereas in case of phosphate buffered saline control revealed roughly 70% HSV‐1 entry into cells (Figure 6f–i).

Figure 6.

ZnO micro nano structures (MNSs). Synthesis of the ZnO material can be done in large quantities, please note the a) 23 mm diameter coin. b) Microscopic image, comparison between A) a standard powder and B) the material synthesized here. c) Electron micrograph showing the complex geometries. d,e) The powder contains a larger quantity of filopodia like structures, which have spikes down to the nanoscale. UV‐illumination on ZnO MNSs significantly enhances HSV‐1 binding. ZnO‐MNSs were exposed to UV illumination for 30 min. MNSs were stained as red via phalloidin treatment (panel f); UV untreated (panel g) and UV‐treated (panel h) ZnO MNSs were mixed with green fluorescent protein (GFP)‐tagged HSV‐1 (VP26); The UV exposed ZnO‐MNSs showing significant HSV‐1 trapping as indicated by strong yellow co‐localization signal (highlighted by arrows) compared to UV‐untreated red‐ZnOMNSs. i) Pre‐incubation of UV‐treated ZnO MNSs with HSV‐1 significantly blocks viral entry. In this experiment, b‐galactosidase‐expressing recombinant virus HSV‐1 (KOS) gL86 (25 pfu/cell) was pre‐incubated for 90 min with the UV pre‐treated (+) or untreated (−) ZnO‐MPs at 0.1 mg mL⁻¹. HSV‐1 KOS gL86 mock‐incubated with 1× phosphate buffer saline (PBS; black bar) was used as positive control. The uninfected cells were used as negative control (grey bar). After 90 min the soup was challenged to CF. After 6 h, the cells were washed, permeabilized and incubated with ONPG substrate (3.0 mg mL⁻¹) for quantitation of b‐galactosidase activity expressed from the input viral genome. The enzymatic activity was measured at an optical density of 410 nm (OD410). The value shown is the mean of three or more determinations (±SD). Reproduced with permission.^{[ 15 ]} Copyright 2011, Elsevier.

In another work, Pirkooh and co‐workers exploited inhibition of H1N1 influenza virus using PEGylated ZnO nanoparticles as well as bare ZnO nanoparticles.^{[ 60 ]} Where it was identified that, after exposure of influenza virus with PEGylated ZnO and bare ZnO‐NPs at the maximum non‐toxic concentrations 2.8 and 1.2 log10 TCID50 decrease in virus titer when compared to the virus control, respectively (p < 0.0001). At a maximum non‐cytotoxic concentration of 200 and 75 µg mL⁻¹, PEGylated and non‐PEGylated ZnO nanoparticles inhibited 94.6% and 52.2% virus, respectively. Additionally, they observed that there is significant decrease in fluorescence emission intensity in viral‐infected cell treated with PEGylated ZnO nanoparticles compared to the positive control, which confirms the antiviral activity of ZnO nanoparticles.

Concerning about the current scenario of COVID‐19 pandemic, Ducker and co‐workers reported reduction of SARS‐CoV‐2 infectivity in presence of ZnO coatings.^{[ 61 ]} They employed a variant of the Stöber sol‐gel method to create a form of coating consist with submicrometer‐sized ZnO particles, whereas in another they method they used polyurethane to immobilize zinc oxide tetrapod particles. Both of the system minimized viral infectivity within 1 h; more precisely the viral titer of SARS‐CoV‐2 was decreased by 4 logs, which is a reduction of at least 99.9% compared to uncoated glass. Their coatings system can be applied to a variety of objects, such as hand rails and door knobs, to prevent the transmission of disease. In another recent study, El‐Megharbel et al. also evaluated ZnO nanospray for disinfection against SARS‐CoV‐2.^{[ 62 ]} They have used the synthesized ZnO nanoparticles in 10% DMSO and double distilled water for estimation of antiviral activity against SARS‐CoV‐2 using cytotoxicity assay (CC₅₀) as well as inhibitory concentration (IC₅₀). Their results indicated that, ZnO nanoparticles possess high anti‐SARS‐CoV‐2 activity at cytotoxic concentrations in vitro with non‐significant selectivity index (CC₅₀/IC₅₀ ≤ 1; IC₅₀ = 526 ng mL⁻¹; CC₅₀ = 292.2 ng mL⁻¹), which make it one of the suitable candidates for anti‐SARS‐CoV‐2 coatings applications.

4.4. Titanium Dioxide

Titanium dioxide (TiO₂) is a prevalent metal oxide photocatalysts with a large band gap of 3.2 eV along with a significant potential to finetune its band gap according to field of applications. TiO₂ exists in nature three different forms a) rutile, b) anatase, c) brookite, where rutile is the most common and stable form. While the anatase form is more capable for photocatalytic applications but due to high photoactivity of anatase form, it is not suitable for exterior applications as it losses the protective films after sometime. As shown in Figure 7a when TiO₂ exposed to light of energy equal to or greater than its band gap, there is an excitation of electrons from its valance band (VB) to conduction band (CB). This photoactivated holes and electrons are highly oxidizing and reducing in nature and reacts with oxygen (O₂) and water vapor (H₂O) present in ambient atmosphere and subsequently produces superoxide anions (•O₂ ⁻) and highly reactive hydroxyl ions (•OH). These highly reactive radicals are the primary reason of the photocatalytic effect of TiO₂.

Figure 7.

a) ROS generation of •OH and •O₂ ⁻ after UV light irradiation of TiO₂. b) Mechanism of photocatalytic inactivation of bacteria and viruses. Reproduced with permission.^{[ 63 ]} Copyright 2021, MDPI.

As discussed in above TiO₂ possess strong oxidative effect under appropriate light and this photocatalytic oxidative effect is utilized as photocatalytic disinfectant in biomedical sector. TiO₂ based photocatalytic disinfectants are very effective against antimicrobial as well as antiviral applications in ambient conditions with significant potential that it can be employed in indoor places also. Some of the early studies of TiO₂ based antiviral applications include photo deactivation of virus. In presence of UV light, the ambient moisture (H₂O) and oxygen (O₂) present at air decompose on the TiO₂ surface resulted into ROS such as •OH and •O₂ ⁻ which serve as a highly oxidizing and reducing agents resulting into disintegration of the organic envelope as well as phospholipid of non‐enveloped/enveloped of viruses as showed in Figure 7b.

For instance, one of the early studies, Hajkova et al. evaluated multifunctional photocatalytic effect of TiO₂ thin films against herpes simplex virus‐1 (HSV‐I).^{[ 14 ]} Under UV irradiation and dark the antiviral effect of TiO₂ on HSV‐1 viruses was evaluated by immunohistochemically detection of replication of viral gC protein. The parts A and B in Figure 8 show the dark brown color, which is an indication of replication of the virus in the LAP cells without TiO₂ in UV illuminated condition and with TiO₂ in dark respectively; whereas C and D represent two different types of TiO₂ glass slides in presence of UV. They noticed that after 6 h of UV irradiation, TiO₂ thin films demonstrated outstanding antiviral activity against the viruses HSV‐1, with 100% disinfection. The antiviral activity of TiO₂ was attributed to virus interaction with the TiO₂ surface, which caused significant changes in the virus structure, resulting in the virus's inability to attack host cells. Nankao et al. also evaluated the photocatalytic inactivation of influenza virus by TiO₂ thin film in presence of UV light.^{[ 64 ]} Where they noticed that, denaturation of viral proteins depends on UV intensity as well as UV irradiation time. Furthermore, they found that even with a low intensity of UV‐A (0.01 mW cm⁻²) a viral reduction of approximately 4‐log₁₀ can be achieved within a short irradiation time.

Figure 8.

Antiviral effect of TiO₂ films‐reaction of cell cultures infected by virus HSV‐1. Control sample 1: A) virus on sample without TiO₂ film placed in dark. Control sample 2: B) virus on sample without TiO₂ film UV illuminated. C,D) Virus on two different TiO₂ samples (TiO₂ film from temperature series deposited on microscopic glass slides at a substrate temperature of 155 °C (sample X) and 280 °C (sample Y)) with TiO₂ film illuminated with UV light. Reproduced with permission.^{[ 14 ]} Copyright 2007, Willey.

To further enhance the antiviral activity of TiO₂ under visible light, researchers have modified TiO₂ for both indoor and outdoor applications. For example, Cho and co‐workers prepared fluorinated TiO₂ for ambient light‐activated virucidal surface coating against human norovirus and murine norovirus.^{[ 65 ]} They identified that, in case of fluorinated TiO₂ under common fluorescent lamp for 60 min there is significant reductions in the norovirus surrogates of 2–3 log₁₀ whereas in case of bare TiO₂ surfaces in identical environments it is over two orders of magnitude lower. In another study, Levina et al. synthesized a nanocomposite with titanium dioxide nanoparticles and polylysine (PL)‐containing oligonucleotides and evaluated its efficacy against H1N1, H5N1, and H3N2 subtypes of influenza A viruses.^{[ 66 ]} The nanocomposite efficiently performed against site specific inhibition of influenza virus without any UV irradiation. Vorontsov and his team also evaluated the antiviral efficacy of TiO₂ and platinized sulfated TiO₂ (Pt/TiO₂) against influenza A (H3N2) virus.^{[ 67 ]} In the presence of UV irradiation Pt/TiO₂ demonstrated better antiviral activity (99.8%) toward H3N2 due to presence of Pt compared to undoped TiO₂ (90%). Moreover, it was also reported that the Pt/TiO₂ system also highly operative against the H3N2 virus in dark too. This better deactivation of virus attributed to a better charge carrier separation in the doped semiconductor photocatalyst (Pt/TiO₂) compared to undoped one.

As discussed in above sections due to increasing viral infections of COVID‐19 there is an urgent need of multifunctional materials with antiviral properties to combat with SARS‐CoV‐2 which could be possibly used in hospital environments and transportation services to stop the spread of infections arising from physical surfaces.^{[ 68 ]} Since it has been established that illumination of TiO₂ photocatalysts generates highly reducing/oxidizing free radicals with excellent anti‐microbial/viral activity against various microbes and viruses such as influenza virus, which is transmitted via aerosol and causes respiratory tract infection, similar to COVID‐19, so it has been expected that TiO₂ also work against SARS‐CoV‐2. In this regard, photocatalytic effect of TiO₂ nanoparticles was explored for deactivation of SARS coronavirus in some of the recent studies.^{[ 69} , ⁷⁰ , ^{71 ]} For example, Aida and co‐workers reported SARS‐CoV‐2 disinfection of air and surface contamination using TiO₂ Photocatalyst.^{[ 69 ]} They observed that, in the presence of a 405 nm LED and TiO₂ photocatalyst, the infectivity of SARS‐CoV‐2 decreases in a time dependent manner and reduces its infectivity by 99.9% after 20 min and 120 min of treatment in aerosol and liquid, respectively. The mechanistic findings revealed that, significant reductions in total virion count, increased virion size, and reduced particle surface spike structure as shown in Figure 9 .

Figure 9.

Changes in SARS‐CoV‐2 virion morphology due to LED‐TiO₂ photocatalytic reaction. SARS‐CoV‐2 (1 mL) titer of 1.78 × 106 TCID₅₀ mL⁻¹ was placed on TiO₂‐coated sheet and subjected to photocatalytic reaction for 120 min before TEM imaging. a) Representative virion images in the TiO₂ + Light, Light, and control groups are shown. Bar = 100 nm. b) Number of S proteins on single virions in individual TEM images of the TiO₂ + Light, Light, and control groups was counted, and distribution and mean number of S protein/virion are shown; n = 50/group. c) Each dot represents a value of S protein of each virion in (b). d) Virion number in an area of 170 µm² in an individual TEM image is shown; n = 10. e) Diameter of single virion in an individual TEM image is shown; n = 40. f) Viral titer in each group was confirmed by TCID₅₀ assay. Each column and error bar represents the mean ± SD of results. All values were analyzed by two‐way ANOVA followed by Tukey's test. Asterisk indicates a statistically significant difference (*p < 0.05; **p < 0.01; ***p < 0.001). Reproduced with permission.^{[ 69 ]} Copyright 2021, MDPI.

Khaiboullina et al. examined the effectiveness of TiO₂ nanocoatings toward inactivation of SARS‐CoV‐2 upon UV‐C irradiation.^{[ 71 ]} Their preliminary results based on quantitative RT‐qPCR and virus infectivity assays suggests that, the TiO₂ nanocoating system capable of inactivating a close genetic relative of SAR‐CoV‐2, HCoVNL63 under the influence of UV radiation within 1 min. In another study, Micochova et al. studied stability of pseudo‐SARS‐CoV‐2 virions based on a lentiviral system, as well as fully infectious SARS‐CoV‐2 virus in presence of TiO₂ and Ag‐TiO₂ surface coating on the ceramics tiles,^{[ 72 ]} where they observed that there is no significant difference for TiO₂ and TiO₂‐Ag coatings. In the case of pseudo‐SARS‐CoV‐2, it was found that there is a reduction by four orders of magnitude on both type of coatings. On the other hand, for SARS‐CoV‐2 virus there is significant inactivation on TiO₂ surfaces after 20 min of ambient laboratory light illumination and after 5 h no detectable active virus remained on the surface. Whereas, SARS‐CoV‐2 on the untreated surface was still fully infectious at 5 h post‐addition of virus. Based on their results it can be proposed that TiO₂‐based coatings system can be employed in combatting SARS‐CoV‐2, specifically in health care facilities where chances of nosocomial infection rates are quite significant. While most of these studies focused on antiviral properties of TiO₂ in present of UV light/ normal LED light/normal sunlight. In a very recent study Miyauchi and co‐workers designed a TiO₂‐based photocatalyst which can inactivate SARS‐CoV‐2 in indoor‐light conditions as well as in dark conditions also.^{[ 73 ]} Briefly they prepared a copper oxide nanoclusters grafted with titanium dioxide (Cu _x O/TiO₂), where Cu _x O nanoclusters consist of a mix valence number oxides in which both Cu(I) and Cu(II) are present that work under dark conditions while its performance is improved by white light illumination due to presence of TiO₂. Here the Cu(II) species in Cu _x O delivers the visible light driven photocatalysis, while the Cu(I) species play a vital role to neutralizing virus proteins which ultimately leads to inactivation of viruses under dark conditions. All the α variant, β variant, γ variant, and δ variant of SARS‐CoV‐2 are inactivated after 2 h of visible light irradiation in presence of Cu _x O/TiO₂ photocatalyst; while under dark condition δ variant took almost 3 h to deactivate. The Cu _x O/TiO₂ photocatalyst not only denaturalizes spike proteins but also fragmented RNAs in the SARS‐CoV‐2 virus, which was supported by sodium dodecyl‐sulfate polyacrylamide gel electrophoresis (SDS‐PAGES), enzyme‐linked immunoassay (ELISA), and quantitative reverse transcription polymerase chain reaction (RT‐qPCR) analyses. This product already commercialized (NAKA CORPORATION, Tokyo Japan) and very soon to be applied in indoor environments, such as hospitals, airports, metro stations, and schools, as an antiviral coating material.

TiO₂ with different morphology, such as nanoparticles (NPs), nanotubes (NTs), and nanowires (NWs), have also been studied and engineered for enhanced photocatalytic antiviral effects to effectively inactivate viruses such as the SARS‐COV‐2 virus. For example, Hamza and co‐workers reported inactivation of SARS‐CoV‐2 in presence of TiO₂‐NTs which exhibited strong anti‐SARS‐CoV‐2 activity at very low cytotoxic concentrations in vitro with a non‐significant selectivity index (CC₅₀/IC₅₀ ≤ 1) along with outstanding antiviral activity at a very low concentration (IC₅₀ = 568.6 ng mL⁻¹), which comes to a conclusion that these TiO₂ nanostructures are worth for coatings applications as a potent disinfectant to combat SARS‐CoV‐2.^{[ 74 ]} In another work, Forro and his team members evaluated TiO₂‐NWs based air filter for personal protective equipment (PPE) and also for a new generation of air conditioners and air purifiers against a set of pathogens.^{[ 75 ]} The TiO₂‐NWs demonstrated excellent photocatalytic activity due to ROS generation under UV exposure which ultimately leads to outstanding antiviral activity; additionally, the TiO₂‐NWs exhibited excellent wettability by the water droplets carrying the pathogens. Using such TiO₂ nanostructures, it could be a promising way to make easily sterilizable air filter/coating systems with excellent antiviral activities to be utilized as an effective preventative tool against the rapid spread of SARS‐CoV‐2 and other coronaviruses.

4.5. Other Antiviral Nanoparticles

Other than the above mentioned common antiviral nanostructures there are certain nanoparticles such as gold, magnesium, silica, perovskites, graphene nanomaterials also emerging as a new class of antiviral materials. In this section of review, we have highlighted use of these nanomaterials toward antiviral applications. Gold nanoparticles (AuNPs) also exploited with combinations of other metals or functionalized with specific ligands for antiviral applications. But due to the extremely high price of gold they are not popular for large scale applications. For example, Yang and co‐workers gold/copper sulfide core shell nanoparticles for antiviral applications against norovirus GI.1 (Norwalk) virus‐like particles that replicate the activity of human norovirus in solution.^{[ 76 ]} Their study provided a detailed understanding about capsid disintegration and mechanism associated with viral deactivation which revealed that, there is a direct link between nanoparticle concentration and treatment time on viral deactivation. Gianvincenzo et al. exploited sulfate ligand functionalized gold nanoparticles (AuNPs) for anti‐HIV applications.^{[ 77 ]} The sulfate‐ligand functionalized AuNPs were able to bind to HIV and inhibit in vitro viral contamination. In another recent work, Stellacci and co‐workers explored a board spectrum non‐toxic antiviral AuNPs with a virucidal inhibition mechanism.^{[ 78 ]} Here they employed two differently functionalized AuNPs for antiviral applications. The first one is 3‐mercaptoethylsulfonate (MES) coated AuNPs and the second one is undecanesulfonic acid (MUS)‐containing ligands. They noticed that, both of the nanoparticles inhibited heparan sulfate proteoglycan dependent viruses, either enveloped (HSV, RSV, lentivirus, and dengue virus) or naked (HPV). However, the effect of the MES‐AuNPs is lost upon dilution whereas all MUS‐functionalized AuNPs demonstrate a clear irreversible effect.

Recently silica‐based nanoparticles also gaining popularity due to its low cost (compared to other antiviral nanoparticles), facile synthesis process and excellent antiviral capability. For example, Botequim et al. synthesized cationic surfactant didodecyldimethylammonium bromide (DDAB) functionalized silica nanoparticles (SiNPs) and evaluated its antiviral capabilities against influenza A/PR/8/34 (H1N1) virus.^{[ 79 ]} They observed complete inactivation of H1N1 virus takes place in presence of glass coated with DDAB‐functionalized‐SiNPs. More interestingly, the DDAB‐functionalized‐SiNPs does not require leaching of DDAB from the silica surface but instead of cationic nature of the surfactant it attract viruses on the SiNPs and destabilizes its capsid and inactivate them. Similar type of work also done by, Cardoso and co‐workers, where they reported surface modified SiNPs for HIV inhibition.^{[ 80 ]} Briefly, here they functionalized SiNPs with three different molecules including (3‐aminopropyl)triethoxysilane (APTES), (3‐glycidyloxypropyl)methyldiethoxysilane (GPTMS) and trimethoxy‐(2‐phenylethyl)silane (TMPES), where APTES functionalized SiNPs are most effective against HIV compared to GPTMS and TMPES functionalized SiNPs. This is most probably due to the cationic nature of ‐NH₂ present on the APTES functionalized SiO₂. In another very recent work, Osminkina and co‐workers exploited antiviral activity of porous SiNPs against different pathogenic human viruses.^{[ 81 ]} They have chosen influenza virus, poliovirus, west Nile virus, hepatitis‐a virus and HIV virus for their study. When treated with the SiNPs, the infectious activity of the virus‐infected fluid is strongly suppressed. In a more specific way, a nonspecific interaction of the SiNPs and viruses has resulted into deactivation of 99.99% of viruses, these studies suggests that SiNPs also can be used for antiviral coating applications.

Other than AuNPs and SiNPs, 2D nanomaterials such as graphene nanomaterials also gained popularity for tackling SARS‐CoV‐2 due to its antiviral properties. There are already few studies where the antiviral properties of graphene and related materials are investigated.^{[ 16} , ⁸² , ^{83 ]} For example, one of the early studies related to graphene for antiviral applications was done by Han and co‐workers; where they exploited how the sharp‐edged structure and charge of graphene oxide (GO) influence the antiviral activity.^{[ 16 ]} In this work, authors have examined a broad spectrum antiviral activity of GO against pseudorabies virus (PRV, a DNA virus) and porcine epidemic diarrhea virus (PEDV, an RNA virus). Where they observed that, GO significantly reduced the infection of PRV as well as PEDV for a 2‐log reduction in virus titers at noncytotoxic concentrations.

The potent antiviral activity of GO is due to its unique layered structure and negative charge. To further confirm the impact of charge of GO in antiviral activity they conjugated cationic polymer poly(diallyldimethylammonium chloride) (PDDA) and nonionic polyvinylpyrrolidone (PVP) with GO. Where they observed that, the cationic GO‐PDDA possess no antiviral activity, but the nonionic GO‐PVP demonstrate similar antiviral activity as GO, which is consistent to bare GO which confirms the negative charge is of GO is an essential requisite for the antiviral action of GO. Later in 2016, Chen and co‐workers also evaluated the antiviral activity of bare GO and GO along with silver(Ag) in the form nanocomposite (GO‐Ag) against both non‐enveloped and enveloped viruses.^{[ 83 ]} They found that, although GO and GO‐Ag both are effective against viruses but GO‐Ag are more superior compared to GO as it work in a synergistic way on the viruses. Virus inhibition assay revealed that, GO‐Ag reduced 25% of infection by Feline Coronavirus an enveloped virus (FCoV) and 23% by Infectious Bursal Disease Virus a non‐ enveloped virus (IBDV), whereas GO only inhibited 16% of infection by FCoV but showed no antiviral activity against the infection by IBDV. They proposed two different mechanisms for antiviral action for enveloped and non‐enveloped virus. The probable mechanism of antiviral action of GO and GO‐Ag is shown in Figure 10 .

Figure 10.

A) Schematic for the antiviral mechanisms of graphene oxide (GO) against the enveloped virus. B) Graphene‐silver nanocomposites (GO‐Ag) against the enveloped virus. C) GO against the non‐enveloped virus. D) GO‐Ag against the non‐enveloped virus. Reproduced with permission.^{[ 83 ]} Copyright 2016, MDPI.

In the context of recent COVID‐19 scenario, Fukuda and his group members examined the interactions of SARS‐CoV‐2 with GO.^{[ 84 ]} Briefly, they tested three different variants of SARS‐CoV‐2; Wuhan, B.1.1.7 (UK variant), and P.1 (Brazilian variant) with GO. Plaque assay and real‐time reverse transcription polymerase chain reaction (RT‐PCR) revealed that 50% and 98% of the virus in a supernatant can be reduced in presence of GO (100 µg mL⁻¹) for 1 and 60 min, respectively. Furthermore, TEM images revealed that, the decomposition of novel coronavirus takes a two‐step virus inactivation mechanism that includes adsorption of the positively charged spike proteins of SARS‐CoV‐2 on the negatively charged GO surface followed by deactivation of the SARS‐CoV‐2 on the surface of GO through destruction of the viral protein. As the interaction of S proteins of SARS‐CoV‐2 with human angiotensin‐converting enzyme 2 (ACE2) is required for SARS‐CoV‐2 to enter into human cells. These studies suggests that graphene nanomaterials also can be employed for antiviral coatings applications.

Perovskites are another emerging candidate for antiviral applications; although they are not that much popular for antiviral applications but due to their excellent oxidative ability, they possess significant potential for antiviral applications. In this regard, one of the very few studies reported by Wang et al. demonstrated spontaneous as well as continuous anti‐viral disinfection of influenza A virus (PR8) using nonstoichiometric perovskite‐type lanthanum manganese oxide La _x MnO₃ (x = 1, 0.95, and 0.9).^{[ 85 ]} The authors utilized the outstanding oxidative properties of La _x MnO₃ (x = 1, 0.95, and 0.9) which damages viral envelope proteins; thus, envelope proteins are denatured and infectivity of the virus is neutralized. One of the main advantages of that, unlike TiO₂ this process does not require external energy sources like light or heat. It was also observed that, the efficiency of disinfection was regulated by oxidative capability of La _x MnO₃ (x = 1, 0.95, and 0.9); using electron paramagnetic resonance (EPR) and temperature programmed reduction (TPR) measurement it was found that La_0.9MnO₃ own the highest oxidative ability (76% disinfection of influenza A virus within 15 min) and subsequently deliver the best disinfecting results within three nonstoichiometric compounds.

Other than these, recently viral receptor modified nanoparticles also appeared as a novel candidate for antiviral applications. For instance, in a recent study Pang and co‐workers reported an antiviral agent (ganciclovir)‐loaded poly (lactic‐co‐glycolic acid) (PLGA) nanoparticles coated with a “double‐lock” hybrid cell membrane abundant with integrin‐β1 and angiotensin converting enzyme II (ACE2) for long lasting antiviral ocular surface preparation.^{[ 86 ]} They observed that, enhanced retention of coated nanoparticles on the ocular surface due to the steady adhesion enabled by specific binding of integrin‐1 with RGD sequence on the fibronectin of the ocular epithelium. Meanwhile, the resulting nanoparticles demonstrated a dual antiviral effect on SARS‐CoV‐2, which is attributed to the inhibition potency of loaded antiviral agents as well as the ability of exposed ACE2 to neutralize and block viral invasion. Although the authors did not perform the effect of these nanoparticles on SARS‐CoV‐2 seated on our daily used surfaces but this type of novel concept to design antiviral nanoparticles provide a versatile platform for topical long‐acting protection against viral infection.

5. Critical Challenges, Emerging Technologies, and Future Perspective

In the above sections different antiviral agents and coating solutions that possess some sort of antiviral properties are summarized. Although these technologies are successful for deactivating viruses on various objects, but still they lack in several factors which restrict their real‐life applications and this is the main reason only very limited numbers of products are commercialized till now. For example, most of these antiviral testing (including SARS‐CoV‐2) carried out in controlled experimental conditions whereas in practical scenario a rigorous and stringent conditions are there. In outside environment, dust may be a major issue which can affect the long‐term efficacy of these antiviral nano materials. If after installation of these nanocoatings it is covered by dusts then viruses may not be affected by these nanocoatings and subsequently viruses can easily transmit through these nanocoatings. So, during design stage of such nanocoatings self‐cleaning should be an important criterion, which should be taken care in mind. Additionally, most of these nano coatings system demand long incubation time with the attached virus (which is applicable for SARS‐CoV‐2 also) for complete disinfection which does not meet the practical requirements. Another major issue is upscaling of these antiviral nanomaterials from lab to industry along with the cost of production. Furthermore, sustainability of antiviral properties another major issue which should be properly addressed before commercialization of these type of antiviral materials. Because it is not practically feasible to apply a coating material very frequently; so long‐term studies are required before commercialization of these materials. Therefore, in this section of the review I discuss about certain emerging technologies, which can stand alone or with combination of existing antiviral materials that can work in a synergistic way to overcome these challenges.

In this regard, pathogen repellent self‐cleaning surfaces recently appeared as a novel platform for preventing bacterial/viral adhesion and biofilm formation, however there is very limited research takes place on its applicability as an antiviral self‐cleaning surface. Most of these self‐cleaning surfaces inspired by nature such as lotus leaf, butterfly wings, water striders. These systems involve combination ofnanostructures/microstructures and chemical functionality. Due to their unique structural morphology and wetting characteristics these types of surfaces frequently employed to produce self‐cleaning surfaces with different degree of repellency. For example, Mannelli et al. examined how wetting properties of a surface determine the infectivity of influenza A virus.^{[ 87 ]} In their study, they have prepared glass surfaces treated with various hydro‐ and fluorocarbon chain length silanes; where three different wetting conditions are tested hydrophilic/oleophilic, hydrophobic/oleophilic, and hydrophobic/oleophobic. They were able to show that the viral envelope degraded in the last two cases, with the hydrophobic/oleophilic surface displaying the highest level of viral inactivity, with an 80 percent reduction in viral activity, whilst the virus activity on glass was little to none.

In another very recent study in 2021, Yilmaz and co‐workers designed a novel antiviral as well as self‐cleaning matts based on electrospun poly(methyl methacrylate) (PMMA) nanofibers decorated with ZnO nanorods and AgNPs.^{[ 88 ]} Their developed nanofiber possesses multifunctional smart capabilities such as a) antibacterial properties for neutralization of both Gram‐negative and Gram‐positive bacteria, b) antiviral capabilities for inhibition of corona and influenza viruses, c) photocatalytic properties for degradation of organic pollutants, enabling a self‐cleaning protective mat, and d) reusable surface‐enhanced Raman scattering (SERS) substrate for quantitative analysis of trace pollutants on the nanofiber. This type of multifunctional system provides both passive and active protection against bacteria and viruses along with self‐cleaning properties.

In near future, these emerging pathogen repellent self‐cleaning technologies in combination with antiviral materials could potentially be used in a synergistic way to combat with viral contamination of high‐contact surfaces in various settings. Where the pathogen repellent self‐cleaning technologies prevents the majority of the viruses to sit on the surfaces while the antiviral agents deactivate any attached viruses that have not been repelled. Additionally due to self‐cleaning nature, with time (during rain/ manual cleaning) it restores antiviral activity. This type of novel technology can help to significantly reduce the transmission of viruses from fomites to person and then from person to person in long term.

6. Conclusion

In conclusion it can be said that modification of surfaces is an essential part of antiviral research. With the recent COVID‐19 outbreak, there has been a rapid increase in the number of studies which are focused on antiviral surface coatings to combat with transmission of the SARS‐CoV‐2. Some of these technologies already commercialized and few are on the pipeline. It is assumed that several other technologies which are discussed here could be employed as surface coatings to prevent the spread of different types of infectious diseases, including COVID‐19 from various surfaces. However, it is anticipated that researchers should consider certain aspects before designing an antiviral coating system so that it can be commercially viable. For example, rigorous testing ofeach category of viruses, enveloped or non‐enveloped, DNA‐based or RNA‐based, time to inactivate viruses, weatherability of the coating system should be performed so that it can be operative in long term prior to making claims of effectiveness. Additionally, a multidisciplinary research collaboration is needed between scientists, industry, and governments to work together toward this goal. Therefore, as of now when the fourth wave of COVID‐19 is on door, our focus should be on better treatment of COVID‐19, and at the same time regulating the transmission of viruses in such a way so that the chance of spread of the infection is minimum while minimizing patient complications and maintaining life support for every level of individuals.

Conflict of Interest

The author declares no conflict of interest.

Biography

Krishanu Ghosal is currently working as a Post‐Doctoral Fellow at The Wolfson Faculty of Chemical Engineering, Technion‐Israel Institute of Technology. He has completed his B.Sc in Industrial Chemistry and M.Sc. in Applied Chemistry from Ramakrishna Mission Vidyamandira, Howrah, West Bengal, India. During his Ph.D. studies, he worked on “Synthesis of biopolymers from recycled plastic waste and natural resources for tissue engineering applications” at the Department of Polymer Science and Technology, University of Calcutta. His research interests include several diverse fields, including synthesizing novel polymers and nanomaterials for biomedical applications, recycling polymeric materials into value‐added products, etc.

Ghosal K., Tackling COVID‐19 Using Antiviral Nanocoating's—Recent Progress and Future Challenges. Part. Part. Syst. Charact. 2023, 40, 2200154. 10.1002/ppsc.202200154