key: cord-0953735-jbg8ha6l authors: Liang, Lili; Ahamed, Ashiq; Ge, Liya; Fu, Xiaoxu; Lisak, Grzegorz title: Advances in Antiviral Material Development date: 2020-08-21 journal: Chempluschem DOI: 10.1002/cplu.202000460 sha: 0662517bc7c66309e7306b6721119b7de96b0a75 doc_id: 953735 cord_uid: jbg8ha6l The rise in human pandemics demands prudent approaches in antiviral material development for disease prevention and treatment via effective protective equipment and therapeutic strategy. However, the current state of the antiviral materials research is predominantly aligned towards drug development and its related areas, catering to the field of pharmaceutical technology. This review distinguishes the research advances in terms of innovative materials exhibiting antiviral activities that take advantage of fast‐developing nanotechnology and biopolymer technology. Essential concepts of antiviral principles and underlying mechanisms are illustrated, followed with detailed descriptions of novel antiviral materials including inorganic nanomaterials, organic nanomaterials and biopolymers. The biomedical applications of the antiviral materials are also elaborated based on the specific categorization. Challenges and future prospects are discussed to facilitate the research and development of protective solutions and curative treatments. Human society is entering a new pandemic age fueled by factors such as the rise in global travel, intensive urbanization, deforestation and changing agricultural practices, all of which increase the possibility of human exposure to animal species that carry potentially deadly viral infections. [1] Human enteric viruses pose a serious threat for disease transmission leading to illness and death, as the human species are unlikely to have immunity to the emerging viruses. [2] A variety of pathogenic viruses have existed and evolved to cause severe harmful impacts, e.g., Severe Acute Respiratory Syndrome (SARS) and Middle East respiratory syndrome (MERS) epidemics. Besides, H5N1 may be evolving faster than our ability to understand it, becoming harder to predict the occurrence of a human pandemic. [3] The global mortality rate of H5N1 was 63%, peaking as high as 82% in Indonesia. [2] The worldwide epidemic of the Hong Kong influenza (H3N2) in 1968 was reported to be a recombinant virus between human and animal/avian virus, and was even not a mutant virus as previously reported. [4] Thus, human pandemics can result from numerous undetected avian influenza strains in existence that may arise out of recombination at any point in time. [4] In this highly connected world, new viruses are able to spread rapidly, causing devastating effects that science must retool to encounter the possible pandemic threats. [1] Research is vital in developing the technology, systems, and services required to achieve universal health care. [5] The conventional methods of prevention involve vaccines and antiviral drugs. However, the development of a vaccine for a new strain could take from few months to several decades; meanwhile, the virus could spread globally and substantially affect the health care system and the global economy. [6] To date, there have been numerous reports and publications on antiviral materials. Biomedical applications of antiviral materials dominate the literature over food applications. [7] However, antiviral materials have not been widely applied in commercial use for personal protection and safety. Influenza viruses have claimed the lives of millions, causing annual epidemics and occasional pandemics. [6a] In cases of fast-moving pathogens such as influenza viruses and coronaviruses, one of the most basic protective strategies is to prevent viral transmission via human contact and aerial discharge. The current state of the protective care products offers surgical or N95 protective masks that, in most instances, are insufficient to provide adequate protection against viral transmission since the virus is small enough to penetrate the microfibers of most masks. [8] 10.1002/cplu.202000460 Accepted Manuscript REVIEW 3 Viruses are acellular obligate parasites. The life cycle of a virus, or rather, viral replication cycle, consists of six basic stages: attachment, penetration, uncoating, replication, assembly, and virion release (Figure 1 ). [9] Based on the two different virion release methods: lysis and budding, viruses are categorized into cytolytic and cytopathic, respectively. In terms of structures, viruses can be separated into an enveloped and a non-enveloped structure. The enveloped viruses have primarily lipid envelopes, which are less stable in the environment. On the contrary, the non-enveloped viruses are more stable in wastewater and surfaces and remain resistant to disinfectants. [10] Generally, antiviral behaviors could be divided into two categories. One is by interfering in the viral replication cycle as therapeutic agents. The other is by acting as a protective shield against viral infections. Nanotechnology and biopolymer technology have demonstrated to be thriving to deliver essential changes to the development of antiviral therapeutics. [11] The research on antiviral technologies such as the use of metal nanoparticles, [12] carbon-based nanomaterials, [13] organic nanomaterials, [14] nanocomposites, [15] and biopolymers [16] cast new light onto the development of antiviral REVIEW protective solutions. For example, the antiviral properties of the nanoparticles are attributed to their charge, size, shape, surface functionality and composition, forcing interference with the viral replication cycle. [11a] Hence, in this review, we evaluate the latest published literatures on the antiviral materials that exhibit potential as either protective shields or therapeutic agents to prevent or alleviate viral infection. The review also provides information on the current state of the developments in the biomedical applications of the antiviral materials. Challenges and future prospects are discussed in the end to facilitate the research and development of protective solutions and curative treatments. Inhibition action prior to viral entry is one of the most attractive approaches against viral infection because the extracellular intervention is relatively accessible. The attachment of virus to host cells and viral entry are recognition interactions involving specific components on viruses' surface and receptors on the host cell membrane, [17] [18] which are promising targets for viral entry inhibition. Inactivation of viruses prior to entry is the most direct antiviral strategy. This antiviral mechanism is proved via indirect evidence, infection at the early stage of viral replication cycle. [20] As a matter of fact, plenty of materials play their antiviral roles via blockage of viral entry. [13d, 21] Similar to the virus inactivation mechanism, researchers observed the antiviral activities at the early state prior to viral entry and made the speculation upon different results or behaviors. For example, Barras et al. reported a type of surface-functionalized carbon dots (CDs) that could interfere with the entry of herpes simplex virus type 1 (HSV-1). [22] Their results indicated that the modified CDs prevented HSV-1 infection at certain concentrations and by specifically acting at the early stage of viral entry. However, they also claimed that CDs might make a difference in limiting viruses spreading from cell to cell. Gao et al. reported a study on 3,6-sulfated chitosan (36S) inhibiting human papillomavirus REVIEW 5 acid-functionalized gold nanoparticles (AuNPs). This study demonstrated a relatively clear mechanism: the receptor of the target virus fusion protein is sialic acid receptor while the modified multivalent sialic-acid-functionalized AuNPs are expected to compete the binding process and thus inhibit the viral infection. [24] Similar mechanisms were reported in multiple studies, where the specific mechanisms were called competition for the binding of virus to the cell, interfaces with viral attachment, preferential binding to the cell proteins, and inhibition of binding to specific receptors. [25] Despite their slightly different description, the speculated mechanisms are rather similar: antiviral materials compete or inhibit the binding process between viruses and host cells and thus inhibiting viral infections. Specifically, another paradigm can be introduced for enveloped viruses, targeting viral fusion process. Enveloped viruses are one of the major causes of human viral diseases and the viral entry process of all enveloped viruses involves membrane fusion. [26] Vigant et al. summarized this particular aspect in their review article. [26] Briefly, the fusion process consists of viral attachment via cell surface receptors as well as conformation changes of protein and components. Both proteins involve in the fusion process and lipids on virus and host cell membranes are potential targets for broad-spectrum antiviral agents. Relevant antiviral strategies are gaining more attention since the outbreak of COVID-19, as researchers are looking for similarities among pathogenic viruses instead of only developing traditional point-to-point methodology. [27] Numerous antiviral agents targeting the viral envelope were reported, including titanium dioxide (TiO2) nanomaterials, [28] silica nanoparticles (SiNPs), [29] liposomes, [30] peptides, [31] etc. For example, Jackman et al. reported a therapeutic strategy that introduced potential membrane-active peptides targeting against mosquito-borne viruses. [32] Badani et al. summarized recent studies of peptide entry inhibitors against enveloped viruses. [33] Detailed examples will be introduced in the following sections. oxide nanoparticles they synthesized exhibited significant antiviral activities against herpes simplex virus type 1 (HSV-1) via oxidation of viral proteins or degradation of viral genome. Although various antiviral activities were observed at the stages after viral entry, the evidence to identify the exact antiviral mechanisms was still insufficient and remains to be further developed in the future. [37] 3. Detailed description of various antiviral materials Currently, numerous types of inorganic nanomaterials, such as metallic nanoparticles, carbon-based nanomaterials and silica nanoparticles, have intrigued tremendous interest in biomedical applications because of their attractive physical and chemical characteristics, including superior biocompatibility, good stability, unique structures, large surface-area-to-volume ratios. [38] As shown in Table 1 , it was found in many studies that inorganic nanomaterials exhibited comparable or even stronger antiviral effect when compared with traditional pharmaceutical ingredient, [39] significantly improved the antiviral drug delivery efficiency as nanocarriers, [40] or exerted synergistic effect against viruses when in combination with antiviral drugs. [41] Although most of the inorganic nanomaterials possessing antiviral activities were reported to be biocompatible, their potential toxic effects on humans and the environment still require additional attention. For example, AuNPs are generally more biocompatible when compared with AgNPs. [42] One of the possible toxic mechanisms may be due to the release of silver ions from AgNPs and the exact mechanism is still under debate. [43] In this section, we mainly focus on the inhibitory effect of inorganic nanomaterials against various viruses as well as different strategies used to enhance their antiviral activity, stability and biocompatibility. AgNPs are one of the most extensively researched classes of metallic nanomaterials used for antiviral applications. Numerous studies have reported that AgNPs exhibit broad-spectrum antiviral efficacy on different stages of the viral replication cycle. [17, 44] GO and its derivatives have been broadly investigated for biomedical applications owing to their unique physicochemical properties. For example, Ye et al. [13c] reported that the GO nanosheets showed strong antiviral effect against PRV and PEDV, due to their extraordinary single-layer structure and negative surface charge. Based on the antiviral effect of GO, Yang et al. loaded CCM on the surface of β-cyclodextrin functionalized GO and explore their synergistic antiviral effect against RSV infection. The results showed that CCM loaded GO could effectively suppress RSV infection through direct virus inactivation and viral attachment inhibition. [58] CDs are an intriguing type of fluorescent carbon nanomaterial with a size below 10 nm. [59] The surface functionalization of CDs significantly enables them to interact closely with the interface in various biological systems. [60] Though the antiviral research of CDs is still in the initial stage, studies carried so far have already shown the promising antiviral activity of CDs that derived from various carbon precursors. Du et al. synthesized cationic CDs by using CCM as a single-layer carbon precursor and observed that the CCM-CDs exhibited outstanding antiviral activity against PEDV infection. The mechanism analysis revealed that CDs could inhibit virus entry, suppress the synthesis of negative-strand RNA within the virus, hinder the budding of the virus and prevent the accumulation of ROS caused by PEDV infection. In addition, this material could also inhibit viral replication by stimulating the host cells to produce proinflammatory cytokines genes and interferon-stimulating genes ( Figure 4) . The results suggested that CCM-CDs carry the great potential to be developed into a multi-target antiviral agent in the future. [61] Figure 4. Possible antiviral mechanism of CCM-CDs against PEDV infection. Reproduced from reference [61] with permission from American Chemical Society. Other inorganic nanomaterials made of copper, zinc, titanium, silica, iron and selenium were also reported with various antiviral activities, mainly including viral entry inhibition, intrinsic virucidal effect and delivery of antiviral drugs. For instance, SiNPs with hydrophobic/hydrophilic surface properties can interact with specific virus envelope that has similar surface properties. It prevented the contact between the host cell receptors and viral envelope, and significantly reduced viral transduction ability. [62] Similarly, Hang et al. proved that cuprous oxide nanoparticles (CO-NPs) could inhibit HCV infection via interaction with virion surface, therefore interfere with viral attachment and entry. [ REVIEW antiviral experiments of TiO2-NCs against Newcastle disease virus (NDV) showed virucidal efficacy at a minimum dose of 6.25 μg/ml, and the possible mechanism of virus inactivation was by lipid damage in the viral envelope. [64] Mesoporous silica nanoparticles (MSNs) have been widely used as drug delivery systems owing to their large surface area, tunable pore structure, size and shape, as well as ease of synthesis and modification. [65] Recently, LaBauve et al. developed lipid-coated MSNs loading antiviral molecule ML336 against the Venezuelan equine encephalitis virus (VEEV). The MSNs core significantly increased hydrophobic drug loading while t he lipid coating retained the loaded drug, achieving sustained drug release and enhanced material biocompatibility. [66] Organic nanomaterials are equipped with favorable properties such as good biocompatibility, biodegradability, colloidal stabi lity and easy modification, owing to their size, morphology as well as surface characteristics. [113] The organic nanomaterials, including polymeric nanoparticles, lipid-based nanomaterials, dendrimers and micelles, are also extensively evaluated for their antiviral properties. Their inherent virucidal characteristics and capabilities to load therapeutic agents make them suitable candidates for effective virus treatment. Polymeric nanoparticles are usually made of natural or synthetic polymers (Table 2 ) with a size ranging from 10 to 1000 nm. [ [115] Besides, Jamali et al. reported that siRNA-loaded chitosan (CS) nanoparticles effectively targeted virus nucleoprotein to reduce virus infections. Moreover, they also indicated that the intranasal administration of CS/siRNA nanoparticles showed therapeutic effect on mice attacked with a lethal dose of influenza virus, revealing the antiviral activity in vivo. [116] Liposomes are vesicular systems consisting of unilamellar or multilamellar phospholipid bilayers. [117] They have received much attention in the biomedical area owning to their outstanding biocompatibility, biodegradability, drug loading capacity and low toxicity. ChemPlusChem This article is protected by copyright. All rights reserved. liposomes to host cell membranes prevented viral entry and the antiviral activity of SA liposomes on HSV-1 is comparable to that of antiviral drug acyclovir. [118] Solid lipid nanoparticles (SLN) consist of lipids that are solid at body temperature, such as fatty acids and triglycerides. acyclovir. [120] Another interesting study reported a novel virucidal nanodisc which was a self-assembled discoidal planar lipid bilayer wrapped by two copies of amphipathic membrane scaffold protein (MSP) and modified with sialic acid on the surface. Mechanistically, the nanodiscs can bind to influenza virions via sialic acid interaction and then co-endocytosed into host cells. Under low pH endosomal environment, the nanodiscs effectively perforated the viral envelope and lead to virus inactivation. [121] Dendrimers are spherical macromolecules consisting of a central core and three-dimensional branched architecture with abundant end groups. [122] The interior cavity is suitable for drug encapsulation while the exterior surface can be easily conjugated with drugs and targeting ligands. [123] The use of functionalized dendrimers as antiviral agents has been widely explored. For instance, a study has shown that sulfonate-ended carbosilane dendrimers presented virucidal activity against HIV-1 infection through virions inactivation and gp120 shedding. conjugates against influenza A virus (IAV). These conjugates resisted H1N1 induced hydrolysis and protected 75% of mice from fatal attack with H1N1, exhibiting the potential to be further developed as IAV inhibitors in virus treatment. Apart from the inherent antiviral activity of functionalized dendrimers, they also act as efficient nanocarriers for drug delivery. [124] Lancelot et al. reported a type of amphiphilic Janus dendrimers consisting of two dendritic blocks with different end groups. The result showed that these dendrimers could encapsulate camptothecin while maintaining the activity of the drug. From the antiviral studies, the Janus dendrimers exerted effective anti-HCV activity at low camptothecin concentration. [125] Micelles are colloidal systems synthesized from amphiphilic copolymers with particle size at 5-100 nm range. [126] The inner core formed by hydrophobic blocks can encapsulate drugs with poor water solubility, while the outer shell formed by hydrophilic blocks can be readily functionalized with various chemical groups. [127] Over the past years, micelles have attracted considerable attention as a drug delivery system. Hong et al. synthesized a DNAzyme called DrzBS which has the potential to inhibit HBV S gene expression via sequence-specific mRNA cleavage. However, the application of this enzyme was limited due to the lack of an exogenous delivery system. To overcome this challenge, they constructed chitosan-g-stearic acid (CSO-SA) micelles to effectively deliver DrzBS for HBV gene therapy. The results indicated that, compared with common transfection reagent LipofectamineTM, the DNAzyme delivered by micelles exhibited higher HBV inhibition rate and even prolonged therapeutic time to 96h. [128] Nanocomposites can be defined as heterogeneous materials with at least one component that has one, two or three dimensions of nanoscale size. [152] Using combinational nanomaterials for the antiviral applications can effectively integrate the advantages of each component in the nanocomposites, which may exhibit fascinating and potent antiviral activity (Table 3) They demonstrated that the virus was firstly absorbed onto the surface of HA, followed with ROS generation from TiO2 under UV radiation that directly inactivated the virus. [155] In another study, Ishiguro et al. deposited copper ion on their previously developed TiO2coated cordierite foam for air cleaner, which exhibited stronger antiviral and antibacterial activities than that of TiO2-coated cordierite foam. [156] Copper ions were also incorporated in zeolite-textile materials and showed high and rapid inactivation of the avian influenza virus (AIV) H5 subtypes. [15b] Nanofibers are a type of nanoscale fibrous material with high surface-to-volume ratio, facile surface functionalization and excellent mechanical properties, which have gathered great interest for applications in different biomedical fields. ROS production rate, durable activity and high biocidal efficacy, the RNMs possess great potential to serve as a biocidal layer on protective equipment. [159] Monosaccharides, [172] oligosaccharides [173] and polysaccharides [174] and their derivatives [175] are found to possess attractive properties, such as low toxicity, biocompatibility as well as antiviral efficacy. There exist numerous review papers discussing the structural properties and antiviral activities of saccharides, especially the widely studied oligosaccharides and polysaccharides. [175] [176] Some latest research findings are illustrated in this review, and further details can be found in relevant references. Among various marine organisms, seaweeds, also known as algae, are the most abundant source of polysaccharide, especially sulfated polysaccharides. [177] Carrageenans are linear sulfated polysaccharides extracted from red seaweeds, which have been widely investigated as an antiviral agent. [178] Boulho et al. applied both conventional and microwave-assisted extraction (MAE) methods to harvest carrageenans from Solieria chordalis and explored their antiviral ability. Results indicated that by using MAE methods, the extracted carrageenans exhibited better antiviral ability against HSV-1, equal to that of antiviral drug acyclovir. [179] Guo et al. reported and HSV-2 infection while uronofucoidans showed no effect. [180] Sun et al. also reported that fucoidans possessed anti-HSV-2 activity by interfering with the absorption of virions to the host cells. [174] Generally, as shown in Figure 5 , the possible antiviral mechanism of seaweed polysaccharides could be the prevention of virus adsorption into the host cells and/or inhibition of the new virion production inside the host cells. [175] 10.1002/cplu.202000460 ChemPlusChem This article is protected by copyright. All rights reserved. Chitosan is a natural biocompatible and biodegradable biopolymer derived from chitin deacetylation. [181] Sulfated chitosan has shown intriguing biological properties including antiviral effect. [182] also interfere with the cellular PI3K/Akt/mTOR pathway and therefore suppress cell autophagy. [21a] Besides, sulfated chitosan extracted from the cuttlebone of Sepia pharaonic was confirmed with antiviral effect against NDV by binding to virus receptors to prevent viral proliferation in the avian bloodstream. [183] Cyclodextrins are natural cyclic oligosaccharides mainly composed of six to eight glucopyranoside units, with unique ring structure, internal hydrophobic cavity and hydrophilic external surface. [184] The above properties make cyclodextrins become potent candidates in the treatment of viral infection via drug delivery, direct virucidal action or synergistic therapy. Recently, Jones et al. developed a nontoxic cyclodextrin modified with sulfonic acid, exhibiting irreversible virucidal activity against a wide range of heparan sulfatedependent viruses and posing a high barrier for the emergence of drug resistance. [185] In summary, the structural diversity and complexity of saccharides and their derivatives could contribute their antiviral activities at different stages of viral infection processes, revealing considerable potential in future clinical transformation. Antiviral peptides have received much attention over the last few years because of their increasing discoveries of antiviral properties. Such peptides can derive from natural sources, such as bacteria, plants and animals, or can be rationally designed and synthesized. [186] They have been reported to target different stages of the virus replication cycle, and the primary mechanism can be summarized as follows: First, some peptides can interact with the virus or host cells, block viral attachment and prevent viral fusion. Second, several types of peptides present direct biocidal activity by disrupting virus envelope. Third, specific peptides can interact with viral polymerase complex or stimulate immune response to inhibit viral replication. [187] Lately, several reviews have comprehensively introduced the studies of antiviral peptides, [186] [187] [188] readers may refer to those reviews for detailed information. In this section, we mainly focus on the latest development of antiviral peptides. Recently, Mechlia et al. investigated the anti-rabies activity of dermaseptins S3, S4 and their derivatives, which are excreted from amphibian skin glands. The results have shown that dermaseptins not only disrupted the viral envelope before viral entry but also affected downstream stages of the virus replication cycle after infection. Data also showed that S4M4K exhibited the highest therapeutic effect that protected 50-60% infected mice from lethal challenge with Rabies virus (RABV). [16b] In another study, poly-gamma-glutamic acid (γ-PGA), an anionic polypeptide generated from Bacillus species, showed its antiviral efficacy against norovirus infection. After oral administration, γ-PGA can interfere with viral entry and increase IFN-β production, which can effectively suppress virus replication in host cells. [189] Also, β-defensins, a family of endogenous cysteine-rich and cationic peptides, demonstrated broad-spectrum antiviral properties against various viruses, especially influenza virus. [187b, 190] Zhao et al. synthesized different peptides derived from mouse βdefensin-4 and discovered that peptide P9 effectively inhibited influenza A virus (H1N1, H3N2, H5N1, H7N7 and H7N9) and coronavirus (SARS-CoV and MERS-CoV). Mechanism analysis revealed that P9 bound to viral envelope glycoproteins, entered into the cells with the virus and prevented endosomal acidification, which impeded membrane fusion and viral RNA release. [191] 10.1002/cplu.202000460 ChemPlusChem This article is protected by copyright. All rights reserved. In addition, rationally synthesized peptides have also been extensively explored for their antiviral effect. Zhao et al. developed a type of dual-functional peptide TAT P1, loading defective interfering genes (DIG-3) of influenza virus. On the one hand, the delivered DIG-3 significantly suppressed virus replication through cell transfection. On the other hand, the vector TAT P1 showed intrinsic antiviral activity by preventing endosomal acidification. [192] This study has paved the way for developing transfection vectors as promising therapeutic agents in virus treatment. Besides, membrane-active peptide has received much attention over the past years in terms of developing antiviral agents. Many medically important viruses are equipped with lipid envelopes derived from host cell membranes, which play a crucial role in viral structural integrity and become attractive targets for membrane-active peptide. [193] For example, α-helical (AH) peptide is known as a broad-spectrum antiviral agent against a wide range of enveloped viruses via lipid membrane destabilization. [194] Recently, Jackman et al. demonstrated a promising antiviral strategy named 'lipid envelope antiviral disruption' (LEAD), using AH peptide as the template ( Figure 6 ). The engineered peptide could penetrate through the blood-brain barrier and preferentially target at Zika virus, resulting in significantly reduced viral infection in mice model. [31] Previous studies indicated that AH peptide possesses unique size-selective disruptive behavior, [194] [195] which can form pores in highly curved membranes (e.g., small vesicles, viral envelopes) and subsequently contribute to membrane lysis after reaching a critical pore intensity. [196] It was further identified that the flexible conformation of AH peptide enables it to exhibit higher membrane targeting selectivity compared with C5A peptide. [197] The above findings suggest that LEAD strategy opens the door to the treatment of mosquito-borne or other types of enveloped virus infection in a feasible approach. Scheme illustration of LEAD antiviral strategy. Reproduced from reference [197] with permission from American Chemical Society. Infectious diseases caused by viruses are still a major threat to public health and associated with significant economic losses throughout the world. [198] As of 20 August 2020, there have been over 22 million confirmed cases of COVID-19 with 3.5% mortality rate. [199] The successful synthesis (including biosynthesis) of those fascinating antiviral materials may provide new insights into the development of antiviral protection solutions, potential antiviral agents, antiviral drug carriers and antiviral drug delivery systems. Proper antiviral protection can effectively prevent infectious disease, reduce economic losses and save lives. [200] Viruses can spread among humans through direct or indirect contact to blood and other body fluids and/or exposure to respiratory aerosols or droplets from infectious individuals. [201] If there is no vaccine for the specific virus, the best way to prevent spread and infection is to avoid being exposed to the viruses. [202] Non-pharmaceutical interventions, such as facemasks, goggles, gloves, and protective suits have been used to protect against virus infection during a pandemic. [8b, 203] As most viruses range in size from 5 to 300 nm, the pore sizes of materials are critical for antiviral protection. [204] The moisture-proof plastic and rubber are commonly used for the fabrication of goggles and gloves, respectively. Compared with goggles and gloves, protective suits require more soft and comfortable permeable materials. [205] However, porous materials are insufficient for antiviral protection. An antiviral material layer is required for protective suits by providing contact killing against virus either in aerosol or in liquid forms. [206] The antiviral nanoparticles have been mechanically infused into textiles for protective suits and other protective products. [159, 207] 10.1002/cplu.202000460 ChemPlusChem This article is protected by copyright. All rights reserved. Facemasks and respirators are the key pieces of personal protective equipment (PPE) that are generally applied for the protection from the viruses transmitted by respiratory aerosols and droplets. [208] Reusable cloth masks have been widely used by general public and even health care workers globally, particularly in Asia. [209] The efficacy of cloth masks against specific virus infectious threats such as influenza and coronavirus could be extremely limited. And, the common practices such as reuse of masks are discouraged on the basis of public health judgment. Therefore, cost-effective antiviral materials are preferred as the raw materials for disposable facemasks to lower the risk of severe illness from virus infection. Currently, medical masks are recommended for the public to prevent respiratory virus infections. [210] The medical masks, also known as surgical masks, are typically three layers that include outer, barrier and inner layers in sequence. The outer and inner layers are made of non-woven fabric materials, and the barrier layer is made of a melt-blown material. The barrier layer acts as the filter that prevents the virus as well as other microbes and particles from entering or exiting the mask. To increase the antiviral effectiveness, antiviral nanoparticles, such as silver, copper and zinc nanoparticles have been coated as a film on the outer layer of masks to rapidly destroy viruses before entering the barrier layer. [159, 207, 211] Furthermore, an additional antiviral layer has also been developed using antiviral materials to co-support with other conventional layers. The antiviral layer, which placed between outer layer and barrier layer could be made from hybrid materials, such as silver nanoparticle-containing fibers, silver-containing polymer nanocomposites. Besides the medical masks, protective respirators have also been used for antiviral applications. [213] The respirators are tight-fitting protective devices with superior antiviral properties when compared to the medical masks. [214] The N95 respirators have been certified to filter at least 95% of particles that are recommended to the healthcare workers to wear for prevention from contracting the virus. [215] Antiviral materials, such as copper oxide nanoparticles could be impregnated into N95 respirators or coated on the surfaces of N95 respirators with an antiviral layer to further enhance the antiviral performance. [216] Furthermore, elastomeric respirators are reusable devices with exchangeable cartridge filters that offer a viable protection option to healthcare workers for updating respiratory protection programs. [217] Obviously, the application of nanomaterials, nanocomposites or biopolymers with antiviral properties to the structure of elastomeric respirators could offer many potential advantages, such as enhanced antiviral efficiency, reduced disinfection fr equency, and extended wear time. [218] For instance, the graphene containing chitosan nanofibers and daylight-driven rechargeable nanofibrous membranes mentioned in the previous section would become suitable candidates in the filter design. [158] [159] The emergence of various viruses has increased the demand for potential antiviral agents, which can be used to treat viral infections. [219] The antiviral agents are different from viricides and should be relatively harmless to the hosts. [ ChemPlusChem This article is protected by copyright. All rights reserved. the emergence of widespread drug resistance and viral mutation makes developing antiviral agents even more difficult. Research on potential antiviral drugs must therefore be continued, and all possible strategies should challenging. Some antiviral materials, especially biopolymers are promising candidates as antiviral agents. [7, 222] Most biopolymers are isolated from natural sources, which possess low toxicity, less side-effects, renewable supply and biodiversity. These biopolymers could offer complementary and overlapping mechanisms of antiviral action by inhibiting viral replication and/or viral genome synthesis. Compared with standard combinatorial chemistry, these biopolymers have higher chemical diversity and biochemical specificity, providing an important opportunity to find new lead structures that are bioactive against a wide range of viruses. In addition, the structures of the biopolymers can lead to chemical modification with improved antiviral activities. [223] In recent years, researchers have confirmed that some polysaccharides, [222b, 222c] , [224] proteins, [225] peptides, [226] polyphenols, [227] polyand oligonucleotides [228] and some natural products derived materials [229] possess antiviral activities and wide-ranging beneficial therapeutic effects. Specifically, the polysaccharides have emerged as an essential antiviral agent, both in vitro and in vivo. Nevertheless, more studies on structure-activity relationships, mechanism of action, drug metabolism, molecular simulation, and combinatorial chemistry are required for better utilization of those biopolymers for biomedical applications. Besides, some biopolymers, such as sulfated polysaccharides, polyphenols and peptides, can be used as synergistic enhancers to boost the effect of other antiviral drugs. [231] The synergistic effect can reduce the therapeutic dose and toxicity of antiviral drugs, and minimize or delay the induction of antiviral resistance. Currently, antiviral drugs suffer from low antiviral efficacy, low compound solubility, low bioavailability when administered in conventional dosage forms. Short half-lives of active compounds, undesired systemic toxic and side effects hinder the development of antiviral drugs. [232] A variety of carrier systems have been developed for antiviral drugs to improve the effectiveness and specificity of them. By far, the most widely studied antiviral drug carriers are biodegradable materials and nanomaterials. Besides physical immobilization and encapsulation, the conjugation of antiviral drugs to biodegradable polymeric carriers is usually designed by the presence of covalent bond between the water-soluble polymer and the antiviral drug molecule. The concept of polymer-drug conjugates opens up a new perspective for drug carriers in modern pharmacy. [233] Compared with conventional antiviral drugs, the antiviral effectiveness of polymerdrug conjugates can be achieved by either part of the polymeric backbone or the side chains, which offer several attractive advantages, such as improved water solubility and stability, controlled administration, and improved pharmacokinetics and biodistribution. To develop antiviral polymer conjugates, several biodegradable polymers are currently being studied, such as poly(N-(2hydroxypropyl)methacrylamide), lignins, (glycol)proteins, deoxynucleotide and biocompatible dendrimers for reduced cytotoxicity and enhanced activity of antiviral drugs. [234] Advances in nanotechnology have a profound impact on drug carriers, leading to the development of nanomaterials with larger loading capacity and higher targeting accuracy for the treatment of viral diseases. [235] Nanomaterials with antiviral intrinsic activity can be considered drug carriers to enhance the effectiveness of antiviral drugs by synergistic effects. However, they are often related to solubility and bioavailability issues. To overcome these limitations, biodegradable nanoparticles, such as lipid-based nanoparticles and biopolymeric nanoparticles have been commonly used as carriers for antiviral drug delivery in the treatment of various viruses. By using these nanocarriers, it is possible to overcome the problems of many antiviral drugs in conventional dosage forms, which may help to address solubility and dissolution issues, increase the bioavailability of drugs, protect sensitive drugs from degradation, reduce adverse side effects, improve tissue tolerance to drugs and reduce treatment costs. [34b, 236] ChemPlusChem This article is protected by copyright. All rights reserved. makes it difficult to find targets for antiviral drugs that can interfere with the viruses without harming the host cells. In recent years, more and more new antiviral drugs have entered the pharmaceutical market. Therefore, various antiviral drug delivery systems have been used for drug site-specific targeting to enhance the effectiveness of the treatment. The targets are not only specific cells, but also specific organelles for antiviral and antiretroviral therapy. Figure 8 outlines the drug delivery systems most commonly studied for antiviral and antiretroviral therapy. [238] Figure 8. Schematic diagram of antiviral drug delivery systems. Reproduced from reference [238] with permission from Medknow. Among the different materials of drug delivery systems being currently investigated by pharmaceutical scientists, "smart" polymer biomaterials hold a great potential for antiviral drug delivery. [239] As an essential feature of human body systems is their ability to change important properties in response to tiny environmental signals, the development of "smart" polymer biomaterials with biomimetic properties could be applied as intelligent antiviral drug delivery systems. "Smart" polymers, or stimuli-responsive polymers in a more scientific term, are capable of altering their chemical and/or physical properties upon exposure to external stimuli. [239] [240] These materials have been intensively studied over the years for on-demand drug deliveries. The schematic representation of "smart" polymers as a drug delivery system for the transport of active antiviral drugs is shown in Figure 9 . Inspired by viruses trafficking from endo-lysosomes, "smart" polymers have been used as an effective drug delivery system. The stimuli-responsive degradation properties of "smart" polymers have shown great possibilities in exhibiting enhanced release of antiviral therapeutics into targeted cells, even the specific organelles. [241] Figure 9. Schematic representation of a "smart" polymer-based delivery system for the transport of active antiviral drugs. [239] [240] In general, nanomaterials have been used as cost-effective biomedical materials for developing antiviral protective solutions. Antiviral biopolymers exhibit equivalent potential for antiviral applications due to their inherent low toxicity, broad-spectrum antiviral activity, high 10.1002/cplu.202000460 ChemPlusChem This article is protected by copyright. All rights reserved. specificity, effectiveness, wide acceptability, biodegradability, and relatively low production costs. [11c, 242] All the efforts dedicated to the synthesis and characterization of these antiviral materials have paved the way for various biomedical applications. However, it was highlighted that dosage regulation and effectivity need to be addressed before industrial-scale applications. [7] Most studies were in the preliminary stages of testing and implementation. For challenging biomedical applications, such as using antiviral drug carriers and antiviral drug delivery systems, it has been found that the current antiviral materials are far from meeting all the clinical requirements. Nevertheless, antiviral biodegradable nanomaterials and "smart" polymer biomaterials are still expected to solve the related biomedical problems and accelerate the transition to clinical applications. On the one hand, the most important limitation observed is that most of the conclusions derived were based on the observations from the in vitro antiviral studies. Further exploration into in vivo studies with animal and clinical testing are essential to progress towards real biomedical applications. On the other hand, the complexity of interactions during the antiviral activity limits the ability to understand the antiviral mechanism. Currently, most of the reported mechanisms are based on speculations. Although the results from the antiviral studies were conclusive, the underlying mechanism of action remains unresolved due to the lack of sufficient evidence. Profound understandings of the antiviral mechanisms would facilitate precise antiviral material development. The reviewed candidates for the antiviral applications demonstrate significant potential in the fight against future viral pandemics. The use of different virus strains and types further complicates the correlation among studies. The most common viral strains used are HIV and HSV, which restrict the application scope of antiviral materials. It would be ideal to develop and test the antiviral materials on certain viruses that represent each viral category. A universal protocol for such studies would facilitate the applications to a broader spectrum of viral pathogens. It was emphasized that there is an urgent need to develop more effective antiviral therapies to reduce morbidity and mortality. [243] A concerted effort is essential to focus the research towards specific goals of achieving the antiviral materials with desired performance. Amidst the viral infections, there are numerous unexplained factors that determine interspecies transmission, reassortment, humanto-human transmission, and exposure-to-infection ratio of the novel viruses. [3, 6a] The opportunity to observe real-time virus evolution would provide us with invaluable information on the factors that determine pathogenicity and/or transmissibility. [6a] The availability of immense amount of data from the previous pandemics can aid along with the help of automation, artificial intelligence and bioinformatics to direct the development of the research area. In the case of H5N1, Yong reported that 99.9% of the exposed population with antibodies carried in their blood failed to develop the disease. However, rapid viral replication was observed in infected people. [3] The cases were clustered within the genetically susceptible blood relatives while others possessed genetic variants that protected them. [3] The complications in understanding the pattern of viral infection need resolution. The economic cost of the pandemics is high with the loss of lives, loss in productivity, social disruption, and incurred government and medical expenses. For example, the economic cost of the 1957 and 1968 pandemics combined was $32 billion (in 1995 dollars). [244] Hence, it is essential for governments and interested institutions to venture and invest in active research addressing the gap in the field. In principle, the H5N1 can become airborne and unpredictable. [3] Preparedness for such an airborne pandemic could prevent largescale implications. The development and/or evolution of novel viruses are predicted to be imminent that would increase the number of pandemics in the future. The probability of pandemic occurrence increases over time. [244] [245] Moreover, the higher the frequency of pandemics the greater the failure of containment efforts due to the shortage of workforce and resources. [245] Hanvoravongchai et al. studied the pandemic preparedness and health system challenges of six Asian countries including Thailand, Indonesia, Taiwan, Lao PDR, Cambodia and Viet Nam. [246] The shortage of highly skilled workers, insufficient stockpiles of the antivirals and PPE were some of the resource challenges attributed to the developing countries. Unfortunately, it is also suggested that the human understanding of the emergence of pandemics is incomplete and may not be as frequent as indicated by scientists. [245] Further, a WHO report stated that creativity and imagination are essential to the research enterprise with new ideas emerging to resolve health problems. [5] It emphasized that the constraints are in the means to implement these ideas and highest quality research into dependable and practical applications to facilitate better health. Research investments are attained by demonstrating results from translatable scientific investigations into accessible and affordable health services. It will be ever more arduous and convoluted to develop antiviral materials with the emergence of new virus strains. The development of novel methods of treatment or inhibition would eventually be overcome by nature (in this case, viruses) over time. Hence, this fight against the viruses will be never ending. 10.1002/cplu.202000460 ChemPlusChem This article is protected by copyright. All rights reserved. ChemPlusChem This article is protected by copyright. All rights reserved. b) M. Vitiello, M. Galdiero, M. Galdiero Nanomaterials for Biosensors Accepted Manuscript ChemPlusChem This article is protected by copyright. All rights reserved Artificial cells, nanomedicine, and biotechnology Accepted Manuscript ChemPlusChem This article is protected by copyright. All rights reserved Sustainable Polymer Composites and Nanocomposites Functional Nanofibers and their Applications Nanofiber Composites for Biomedical Applications Accepted Manuscript ChemPlusChem This article is protected by copyright. All rights reserved 2020, 119689; i) WHO Coronavirus Disease (COVID-19) Dashboard Prevention, N. C. f. I. Diseases, Addressing emerging infectious disease threats: a prevention strategy for the United States Advances in Natural Sciences: Nanoscience and Nanotechnology Google Patents 1-2; b) L. Radonovich 704-720; b) E. De Clercq Antiviral Strategies Accepted Manuscript ChemPlusChem This article is protected by copyright. All rights reserved Google Patents Recent advances in novel drug carrier systems Proc. Natl. Acad. Sci Biotechnological applications of polyhydroxyalkanoates 16-30; b) Biologically-responsive hybrid biomaterials 2010 Marine Organisms as Model Systems in Biology and Medicine Accepted Manuscript ChemPlusChem This article is protected by copyright. All rights reserved The authors would like to acknowledge the Nanyang Environment and Water Research Institute, Nanyang Technological University (Singapore), and Economic Development Board (Singapore) for the financial support of this research In this review, the current state of the antiviral materials research was summarized, categorized, and discussed. It distinguishes the research advances in the development of drug carriers, drug delivery systems, nanoparticles, biopolymers and protective equipment as therapeutic agents or protective shield against virus infections. The authors declare that they have no competing interests. ChemPlusChem