key: cord-0802043-x0sj2lcm authors: Jastrzębska, Agnieszka M.; Vasilchenko, Alexey S. title: Smart and Sustainable Nanotechnological Solutions in a Battle against COVID-19 and Beyond: A Critical Review date: 2021-01-07 journal: ACS Sustain Chem Eng DOI: 10.1021/acssuschemeng.0c06565 sha: 8f2f5ed6eea5d97c74e80ff2e02a29a32fe2491b doc_id: 802043 cord_uid: x0sj2lcm [Image: see text] The variety of available biocidal features make nanomaterials promising for fighting infections. To effectively battle COVID-19, categorized as a pandemic by the World Health Organization (WHO), materials scientists and biotechnologists need to combine their knowledge to develop efficient antiviral nanomaterials. By design, nanostructured materials (spherical, two-dimensional, hybrid) can express a diverse bioactivity and unique combination of specific, nonspecific, and mixed mechanisms of antiviral action. It can be related to the material’s specific features and their multiple functionalization strategies. This is a complex guiding approach in which an interaction target is constantly moving and quickly changing. On the other hand, in such a rush, sustainability may be put aside. Therefore, to elucidate the most promising nanotechnological solutions, we critically review available data within the frame of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other types of viruses. We highlight solutions that are, or could be, more sustainable and less toxic. In this regard, reduction of the number of synthetic routes, organic solvents, byproducts, and residues is highly recommended. Such efficient, green solutions may be further used for the prevention of virion–host interactions, treatment of the already developed infection, reducing inflammation, and finally, protecting healthcare professionals with masks, fabrics, equipment, and in other associated areas. Further translation into the market needs putting on the fast track with respect to principles of green chemistry, feasibility, safety, and the environment. A new type of disease was first reported in China close to the end of 2019 and was soon labeled by the World Health Organization (WHO) as pandemic coronavirus COVID-19. 1 Novel SARS-CoV-2 virus was quickly transmissible, allowing it to spread to over 200 countries, infecting more than 40 million people and claiming over a million lives to date. 2 The first infections with SARS-CoV-2 were noticed in the Hubei Province of China. Patients showed symptoms similar to pneumonia and were visualized to have abnormal features in their lungs. Difficulties in clinical recognition caused the necessity of sample screening with a polymerase chain reaction (PCR) within disclosed pathogen control panels. The first obtained results were negative, but further studies with next-generation sequencing, presented at the beginning of 2020, revealed the presence of an RNA virus. 3 Meanwhile, the sequence of the novel virus genome showed similarities to SARS-CoV from the 2002−2003 outbreak. Therefore, it was named severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). 4 The Coronaviridae family includes many species. When compared to the current pandemic, previous SARS-CoV and the Middle East respiratory syndrome (MERS-CoV) coronaviruses were characterized by lower transmission potential which allowed the effective prevention of spreading. It is noted that most of the hundreds of identified coronaviruses are transmissible only between animals, and this reservoir for SARS remains still unexplored. 5 Cross-species transmission is also a specific "gene pool" allowing viruses to generate a new recombinant species. 6 Some of these can adapt to new human hosts. 5, 6 To date, seven coronaviruses are proven to cause human diseases, and three times during recent years they caused a global health emergency. Nevertheless, most of them (for instance, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1) develop a common cold in humans. Before SARS-CoV-2 appeared, SARS-CoV-1 caused severe disease with ∼10% mortality and MERS-CoV caused ∼35% mortality. The most contagious so far is beta-SARS-CoV-2. Its sequence is 96% similar to beta-coronaviruses in comparison to the whole genome found in bats. 7 It is, however, genetically different from other MERS coronaviruses. 8 Pairwise protein sequence analysis revealed its belonging to the SARS-CoV family 9 and various transformations during pandemic spreading. Similar genomes were also identified for beta-CoVs (Wuhan/IVDC-HB-01/ 2019, IVDC-HB-04/2020, IVDC-HB-05/2019, WIV04/2019) and the previous malignant IPBCAMS-WH-01/2019 virus. 6 Therefore, it is likely that the expected consecutive genetical transformations will lead to lower malignancy of the SARS-CoV-2. Because of the low fatality of previous HCoVs, the coronaviral drug discovery and nanotechnological-related studies on their prevention and treatment did not evolve into industrial application. While taking into consideration the significant infectivity of SARS-CoV-2, as well as long-range detrimental effects on human health, filling this gap of knowledge is undoubtedly an emergency. 10 Transmission of SARS-CoV-2 is high in comparison to other coronaviruses because of a long period of latency, high infectivity, and many asymptomatic carriers. It is estimated that in the case of Wuhan, the mean value of risk of fatal development of symptoms (probability of dying) is 1.4%. The risk increases with age, and symptomatic adults between 30 and 60 years old are ∼4% of the patients per year. 11 This means that the majority of persons can be asymptomatic and unaware of spreading the virus. Their daily activities quickly cause personto-person transmission for which the WHO 4 highlights both hospital and family settings as most critical for rapid expansion of coronavirus. 12 This allows for further assumption that it also transmits through contaminated surfaces and self-inoculates within the nose, eyes, and mouth mucous membranes. 13, 14 A recent analysis 15 on aerosol exposure concentrated on swab samples and surfaces of sickbed handrails, computer mice, floors, trash cans, and masks, as well as other personal protective equipment used by patients with severe disease. It also considered indoor air and the air outlets with a 300 L min −1 flow rate for 30 min. The aerosol distribution characteristics showed a transmission distance of up to 4 m. 15 This implies a potentially extraordinary infection risk for people contacting patients with Available data on less contagious airborne endemic human coronavirus 229E (HCV/229E) are helpful to better understand survival rates. These studies were carried out at temperatures of 6 and 20°C and relative humidities (RH) of 30%, 50%, and 80%. It has been noted that at 20°C and 50% RH aerosolized HCV/ 229E virions survived for over 60 h. Afterward, 20% of virions remained contagious for over 6 days. This indicates more a complex role of the environmental features on virus survival than only a low temperature stabilization effect. 16 Indeed, a recent study showed that a 1% decrease in relative humidity of indoor air causes 7%−8% increase in detected COVID-19 cases. In this context, low humidity of air can be critical in virus transmission and survival rates. 17 Other studies on the persistence of coronaviruses 18 showed that copper surfaces inactivate the virus in approximately 4 h. 19 Recent analysis 20 also revealed that SARS-CoV-2 is new to human beings. Therefore, when facing less immunity during the winter season it is likely to transmit more readily. Lack of expected slowing of virus spreading concerning season changing showed that variables in outdoor temperatures are not enough to stop transmission on its own. 21 In this regard, lowering the transmission of SARS-CoV-2 is assumed as the starting point for better control of the COVID-19 disease. The first approach to halt virus spreading covered available disinfecting agents. Suspension tests against the HCoV-229E virus involved concentrated ethanol, isopropanol, a mixture of isopropanol with n-propanol, glutardialdehyde, and formaldehyde. These agents inactivated coronavirus infectivity to some extent. The measured effective disinfection concentration after 1 min of exposure was 0.21% for sodium hypochlorite and 0.5% for hydrogen peroxide in a mixture of concentrated ethanol. In contrast, 0.02% of chlorhexidine digluconate was rather ineffective. 18 Also, benzalkonium chloride, sodium hypochlorite, and ortho-phthalate aldehyde solutions were less effective. 18 Contrarily, the 1 min carrier tests showed that sodium hypochlorite and glutardialdehyde reduced virus infectivity over 3 logs. 18 It has been also noted that the virus infectivity may be reduced by ultraviolet (UV, 254/365 nm radiation, 4016/2133 μW cm −2 emission) light placed at a distance of 3 cm from the surface. 22 It is accepted that smart nanomaterials can help to solve the problem of pathogen infections worldwide. Many studies are promising for development of antiviral solutions. They may significantly contribute to reducing the negative effects of COVID-19 thanks to the variety and diversity of available biocidal features. Some of the developed antiviral nanosystems, 23 34 and vaccine 34,37 development against COVID-19 are also discussed. It should be highlighted, however, that these works provide an interesting overview of various nanomaterials, mostly in relation to the simplified scheme of the virus life cycle. 10 They also concentrate on the most effective solutions for specific working conditions. Meanwhile, the approaches based on the 12 principles of green engineering 38 still remain underrepresented. Constantly postponing sustainability increases concern that better efficiency will result in a long-range undesirable impact on human health and the environment. It is accepted that designing sustainable nanotechnological solutions is challenging. Considering inherently nonhazardous materials and energy inputs/ outputs takes time and must include integration and interconnectivity with available energy and materials' flows. 38 The proposed nanotechnological solutions are not carefully analyzed in terms of sustainability measures. 39, 40 As a consequence, natural, biodegradable, and biocompatible resources are still not widely used in development of nanomaterials. In the context of fighting COVID-19, nanoparticle synthesis methods involving natural and renewable resources are the unquestionable benchmarks. 41 Feasible, nontoxic, and scalable synthesis routes are beneficial to sustainability, as well as selfassembly techniques that are another good example of sustainable approaches. They are based on molecular interactions without chemical bonds breaking or forming. Techniques that allow for better controlling the properties by using building blocks, using reversibility, or providing external stimuli response are therefore a matter of interest for development of nanotechnological approaches against SARS-CoV-2 virus. The resulting amount of synthetic routes and stages is favorably reduced together with the use of organic/toxic solvents and residues. 42 This perspective reports the current potential of smart antiviral nanotechnological solutions in fighting COVID-19. These are, or could be, less toxic and more sustainable. The advantage comes from broad coverage, more clear (specific and/ or nonspecific) systematization, and critical discussion with knowledge on nanotechnology-based antiviral solutions. In the area of mixed modes of action, this work covers promising antiviral nanomaterials that act outside and/or inside the host concerning virus features, spreading pathways, and survival rates. In this regard, it describes development of complex multifunc-tional virucidals, possible variations in mechanisms of action, potential cytotoxicity, and resistance targets viz. the most actual SARS-CoV-2 infection cycle. We believe that this study will increase future awareness of a selection of nanotools for antiviral nanomaterials with rationally designed mechanisms of action that are useful for future fundamental and application studies. In addition, this prespective goes beyond the COVID-19 pandemic, presenting the most promising and sustainable approaches that are already reported for other types of viruses in the hope that they will also find the possibility to confirm their applicability against SARS-CoV-2. In this regard, protection ■ NANOTECHNOLOGY FOR VIRUS PREVENTION AND TREATMENT Development of broad-spectrum antiviral drugs is a great challenge because of the many difficulties in using targeting approaches within virus-specific mechanisms of action. Broadspectrum antivirals can act against many virus species that even exhibit significant differences in structural and phylogenetical natures. The problem of limited action can be solved with nanomaterials that offer properties allowing them to broadly interact with various types of viruses. Smart nanomaterials offering variety and diversity of available bioactive features can be promising for prevention and treatment of COVID-19. 33 They can both prevent the formation of entry complexes at the host surface and provide therapeutic features inside the host after virus entry. The urgent need for finding a universal solution against SARS-CoV-2 has resulted in the preparation of various review papers concentrated on listing already developed antiviral nanosystems, 23−27 as well as emerging ones. [28] [29] [30] [31] [32] 23, 33 These are highly valuable in searching for the most effective solutions in relation to known viruses. The knowledge is now developing so fast that it urgently needs to be revisited. For example, recent elucidation of viral NSP-family proteases such as M pro main cysteine 43 or PL pro pappain-like cysteine protease 44 allows developing new targeting approaches. Also, freshly discovered formation mechanisms of cytosolic double-membrane vesicles armed with crown-shaped molecular pore complexes 45 significantly changes the previously assumed simplified conditions 10 that are currently used for the analysis of nanomaterials' antiviral potential. In this section of the study, the available nanotechnological solutions are critically discussed concerning the newest reported life cycle and unique features of SARS-CoV-2. Many complex approaches developed for nanomaterials concern various antivirals that put at first place the material's properties of finding its explicit influence on the whole viral life cycle. In the simplified scheme of viability observation, the antiviral activity against different types of viruses was demonstrated by inorganic metallic nanocompositions (silver, 46 gold, 47,48 copper 49 ) and metal oxide nanoparticles (NPs) (tin oxide, 50 zinc oxide, 51 titanium dioxide 52, 53 ). Other nanotechnology-based approaches include carbon-based nanostructures (quantum dots, 54,55 graphene 56 ) and organic-based compositions, 57,58 as well as inorganic−organic hybrid systems. 59 In most cases, there is no explicit information on the outcome, for instance, if the virus was irreversibly inactivated or still possessed the infectivity upon dilution. Also, can the observed antiviral effects be extended toward other types of viruses? In this context, defining the right mechanism for nanomaterial antiviral action is rather difficult. Moreover, analyzing nanomaterials in terms of biostatic or biocidal action is also not a fully adequate approach because the main criterion by which substances can be divided into biostatics and biocides is the reversibility or irreversibility of the inhibitory effect after the test object is no longer in contact with the drug. Nevertheless, we have recognized that the available knowledge on nanomaterials bioactivity can be more clearly rearranged into specific and nonspecific groups of mechanisms of action. While using this approach, we can easily distinguish specific or nonspecific behaviors for the described nanomaterials. Moreover, we denote the right signposts and targets for subsequent development of innovative nanotechnological solutions based on a new generation of mixed mechanisms of action, such as those presented in Figure 1 . Below, we give a more detailed explanation of criteria enabling nanomaterials to be classified into a specific or nonspecific group of action. While choosing the right mechanism of action, it is important to answer only three questions. First, is the antiviral action equally effective against a minimum of two types of viruses, for example, enveloped and nonenveloped? Is the nanomaterial intentionally or nonintentionally guided by any nanotechnological or hybrid means to the site of its intensified action? This can be a reaction site localized in/on virus/cell or other places of choice. Finally, does the antiviral efficiency remain upon dilution and/or loss of nanomaterial−virus interaction? In the context of the aforementioned questions, rethinking the mechanisms of antiviral action becomes a rather noncomplicated issue. Therefore, in the case of a specific mechanism of action, the nanomaterial mostly reversibly targets receptors or ligands on the surface of the virus or cell that leads to the prevention of virus−cell interaction. The second group is the nonspecific antivirals which have a destructive effect on various structures of the virion regardless of their taxonomic position and local place of stay. In other words, their action is not externally guided and leads to irreversible deactivation of the virus, also upon dilution. They can be thus safer for patients than those of only the nonspecific group. There is also the third group -mixed-type antivirals. They provide complex bioeffects that are challenging to understand and control. However, they can be also smartly tailored for the on-demand and/or stimuli− response manner of action. Given the above, further discussion was arranged by the type of action (specific, nonspecific, and mixed) to facilitate recognition of mechanisms of action and possible challenges that need to be faced. This is especially important for development of antivirals with mixed mechanisms of action. Finally, we present data in Table 1 arranged by the type of virus to provide better recognition of the powerful nanomaterialbased solutions already verified against HCoV, SARS, MERS, and other viruses of current interest. Such an approach facilitates the need for standardization of nanomaterials that may be promising in development of broad-spectrum nanotechnological solutions. Nanomaterials with a Specific Mechanism of Antiviral Action. Nanomaterials with a specific mechanism of action mostly act outside the host cell by inactivating virus particles before entering through the cell membrane. This contributes to the disruption of the first phase of the virus life cycle. The SARS-CoV-2 particle is not a very complicated structure in comparison to bacteria or mammalian cells. The virus features are schematically presented in Figure 1a . The ∼60−140 nm capsid is covered by a lipid-based viral envelope carrying a single-stranded RNA genome. 60 The construction proteins can be divided into membrane (M), envelope (E), and spike (S), as well as the nucleocapsid (N) which hosts the RNA genome. The S proteins covers the virus surface and form ∼9−12 nm structures. 61 The nucleocapsid additionally contains a wide range of different accessory and functional elements. These include viral NSP-family proteases together with recently discovered M pro main, 43 and PL pro pappain-like cysteines. 44 Binding to viral structural elements is a simple solution that allows development of broad-spectrum, nontoxic antivirals. In such a case, the activity strictly depends on the reversible binding, which relates to the dilution effect mostly caused by the It is worth highlighting that this is also a key mode of action that determines the difference between virustatic and virucidal agents. 62 Further targeting may involve the host cell membrane and associated cell−viral receptors which are targeted by many viruses during the first step of the replication cycle. These are angiotensin 2 converting enzyme (ACE2) 63 and transmembrane serine protease 2 (TMPRSS2), 64 as well as endosomal cysteine proteases (cathepsins). 65 The affinity of SARS-CoV-2 proteases is higher toward ACE2 than TMPRSS2. Preventing the binding to glycoproteins and their further inactivation is another good direction for designing smart nanotechnological solutions. Liposome nanostructures can be used here for this purpose. While being nontoxic and of natural origin, they can be substantially used for transportation of synthetic receptor glycan sialyl neolacto-N-tetraose c (LSTc)sialoside that can bind and deactivate the influenza A virus. 58 Influenza glycoprotein hemagglutinin (HA), as well as neuraminidase (NA), can be also used for liposome functionalization. 66 Such prepared liposomes attach to binding sites and further release the antiviral drug Oseltamivir. 67 The recent study using computational approaches revealed the specific binding features of the SARS-CoV-2 spike protein which is positively charged because of a majority of positively charged residues versus a minority of negatively charged ones. As a consequence, interactions between spike proteins and ACE2 receptors showed a 30% higher energy binding in the case of SARS-CoV-2 than previous SARS-CoV. These results are useful not only for understanding the mechanism of cell entry but also for designing the targeting nanoagents. 68 Nevertheless, based on previous evidence and experience with SARS and MERS, the primary focus has been the S protein, 69 considered as the ideal target for future COVID-19 nanotherapies. While searching for new antiviral nanomaterials, it is noted that two-dimensional (2D) nanostructures also show a large potential in pathogen elimination. This large and diverse group includes graphene family materials (GFMs), 70 2D oxides and hydroxides, 71 transition metal dichalcogenides 72 and nitrides, 73 2D metal−organic covalent frameworks, 74 ditransition metal phosphides, selenides, and sulfides, 75 as well as Xenes 76 and MXenes. 77 The family of MXenes is the most recent and also prospective member of this group of 2D materials. MXene phases, also known as the early transition metal carbides, nitrides, and carbonitrides were first reported by Naguib et al. 77 While most MXenes were predicted theoretically and only a small portion was obtained experimentally, 78 they have a large potential for further development. MXenes have already demonstrated large application potential in macromolecules adsorption, 79 nanomedicine, 80 and environmental remediation. 81 Since 2016, biocidal features of MXenes continue to be widely developed. 82−84 Recent results reveal their potential in antifouling materials, 85, 82, 86 while their antiviral properties are yet to be explored. Among other 2D nanomaterials, carbon-based nanostructures proved their efficiency in both bacteria and virus elimination. 87 Several advanced nanotechnological solutions that involve GFMs were developed during the previous years that may be extended against COVID-19. 88 A recent study considered the antiviral action of graphene oxide (GO) and reduced graphene oxide (rGO) toward the porcine epidemic diarrhea virus (PEDV) and pseudorabies virus (PRV). 56 ACS Sustainable Chemistry & Engineering pubs.acs.org/journal/ascecg Perspective reduction of the PEDV and PRV infections by GO conjugated with sustainable and nontoxic polyvinylpyrrolidone (PVP). The possible mechanism of action involved the antiviral influence of the negative surface charge of the developed 2D nanostructure, as well as its sharp edges. It is worth mentioning that the zeta potential was previously indicated as a key for interactions of various nanostructures with microorganisms. 89−93 For an antiviral nanomaterial, it should be larger to develop a local gradient of charge or the opposite to the positively charged viral envelope. 94, 95 The considered attachment can be thus much more effective. Sharp edges and zeta potential were also evaluated in the case of GO antiviral activity. 56, 95 It should be stressed that the aforementioned effects may pose a safety risk because strong electrostatic interactions also occur between cell lipid headgroups and graphene oxide. 96 Apart from potential problems with biocompatibility, GO-mediated multiplex interactions can be used for designing on-site disinfection of viruses such as virus of waterfowl (H7N9) and endemic gastrointestinal avian influenza (H9N2). Interestingly, the disinfection by virus entrapment occurs during temperaturedependent GO reduction to rGO and is most efficient at elevated temperatures such as ∼56°C. 97 Nanomaterials with a Nonspecific Mechanism of Antiviral Action. The most desirable property of the ideal antiviral nanomaterial is the nonspecific activity. The expected outcome is the irreversible deactivation of the virus no matter how large the subsequent dilution is. In this regard, detrimental virucidal effects cannot affect the treated cell. The needed selectivity is, therefore, a great challenge and a huge bottleneck in development of nonspecific antiviral nanomaterials. 62 The potential toxicity of nanomaterials is a major concern in this case and needs careful and in-depth studies while designing antiviral nanotherapeutics for fighting respiratory diseases. 98 If nontoxic, nanomaterials can be beneficial in specific targeting and treatment as they should not induce significant resistance. 99 A more detailed discussion of the mentioned aspects is given in the further sections of this perspective. When considering the nonspecific antiviral nanomaterials that act outside the cell, there is the need for development of the binding solution that will allow for obtaining broad-spectrum efficiency. This is of crucial importance for the prevention action against various types of viruses. As a consequence, targeting cell−virus interactions is being developed extensively and concentrates on achieving deactivation of virions through structural elements that are common to most types of viruses. This can be done by interacting positively charged NPs with negatively charged heparan sulfate (HS) groups. 62 They are expressed by the host surface and are cofactors that directly bind with spike proteins to promote viral entry. 100 Therefore, no matter if we consider specific or nonspecific mechanisms of antiviral action, the first gatekeeper for prevention still concerns interactions between the cell and the virus. In this regard, targeting cellular heparan sulfate is promising for development of future broad-spectrum antivirals. While designing antiviral solutions that should work inside the treated host, the uptake is the second stage to consider. It must be effective, with again no harm to treated cells. The internalization mechanism may involve clarithin or caveolaemediated endocytosis, macropinocytosis, or phagocytosis. 101 In this context, the size 102 and shape 101 of the uptaken nanomaterial have a crucial influence on the mechanism of entry. Differences in sizes, physicochemical properties, surface modifications, or the type of treated cells can significantly affect the penetration level and cellular entry. 103 The size of ∼50 nm is optimal for uptake by nonphagocytic cells. 94 In this regard, the specific intracellular microenvironment of action is important to consider 99 and is a matter of interest because it influences the aforementioned interactions. For nonspecific treatment of infections, nanodrugs should first easily enter the host cell and work specifically in its interior to target various stages of viral action. Here, a wide range of different effects can be activated, depending on the type of entry (endocytosis) and further processing of new virions. In this regard, extensive research is needed to develop effective nanomaterial-based antiviral systems, as well as to understand their detailed mechanism of action. On the other hand, broadspectrum therapy is challenging because Coronaviridae are diverse from a biological point of view, as well as rapidly mutate. Nevertheless, some interesting antiviral solutions are already available thus paving the way for more rapid development of nanodrugs against SARS-CoV-2 and other viruses. Antiviral activity toward HCoV-229E, a similar type of coronavirus, was already confirmed for carbon quantum dots (CQDs). The important thing here is the carbon precursor which was used for the synthesis of CQDs and their surface modification. In a recent study, CQDs with a concentrationdependent antiviral activity of EC50 of 52 μg mL −1 were obtained using hydrothermal carbonization of citric acid in a mixture with ethylenediamine. 104 During synthesis, CQDs were subsequently modified with boronic acid ligands. This is important from the activity point of view because the surface modification of nanomaterials has a crucial impact on biological response. 105, 106 Indeed, the pristine CQDs obtained from 4aminophenylboronic acid resulted in obtaining excellent EC50 values below 5.2 μg mL −1 . 54 The mechanism of action involved inhibition of virus entry by interaction with entry receptors and disturbing the viral replication step. Other studies confirmed that CQDs can be successfully used against various types of viruses as broad-spectrum antivirals (Table 1) . Highly biocompatible CQDs synthesized from glycyrrhizic acid by a hydrothermal method were used for deactivation of porcine reproductive and respiratory syndrome virus (PRRSV). 107 Other solutions considered the use of curcumin for the synthesis of cationic CQDs and their verification toward porcine epidemic diarrhea virus (PEDV). 108 Obtained nanostructures inhibited entry and proliferation of viruses by binding with surface proteins and suppressing the synthesis of RNA. Obtained results also indicate that CQDs, apart from halting virus invasion and replication steps, reduce accumulation of intracellular reactive oxygen species (ROS) accumulation, 108 as well as stimulate an antiviral innate immune response. 107 It is further noted that 2D materials can be also used as ROS scavengers. A recent study demonstrates the use of delaminated 2D Nb 2 C and Nb 4 C 3 MXenes modified with poly-L-lysine (PLL) as effective ROS scavenging agents. 105 Another study presents feasible ROS, reactive nitrogen species (RNS), and inflammatory cytokines scavengers based on 2D transition metal dichalcogenides (TMD). Delaminated 2D WS 2 , MoSe 2 , and WSe 2 nanosheets surface modified with polyethylene glycol (PEG) effectively reduced mitochondrial and intracellular ROS and RNS in inflammatory cells. 109 This effect can be highly beneficial for controlling nanomaterials toxicity and should be further investigated also in more complex antiviral systems. While the suppression of viral replication additionally causes overproduction of proinflammatory cytokines and interferon-ACS Sustainable Chemistry & Engineering pubs.acs.org/journal/ascecg Perspective stimulating genes (ISGs), 108 it is important for smart therapeutic nanostructures to minimize the cytokine release (cytokine storm), which is one of the most detrimental effects of COVID-19. 110 Novel nanoparticles were also reported to possess antiviral activity through a different mechanism of action, and gold nanoparticles (Au NPs) are the mostly studied antiviral nanostructure. MERS-CoV can be treated with Au NPs conjugated with the specific peptide called pregnancy-induced hypertension (PIH). It disturbs membrane fusion between virus and host cells mediated by the HR1/HR2 peptide pair. The obtained nanohybrids exhibited better biocompatibility and stability in vitro and in vivo. 111 Respiratory syncytial virus (RSV) can be also successfully inhibited by Au NPs. The nontoxicity is maintained by coating with undecanesulfonic acid (MUS) ligands. MUS ligands also proved their efficiency for designing broad-spectrum antiviral nanomaterials with a nonspecific mechanism of action against both enveloped (HSV, RSV, lentivirus, and dengue virus) and the so-called nonenveloped ("naked") (HPV) types of viruses. 62 Silver nanoparticles (Ag NPs) can be used as oseltamivir carriers toward H1N1 infection by condensation of chromatin, DNA fragmentation prevention, and targeting the caspase-3 function. 59, 112 Human parainfluenza 3 (HPIV-3) was also inactivated with Ag NPs by suppressing replication after blocking the function of cell−virus leveraging. Notably, the inhibitory effect was size dependent and zeta potential dependent. 46 A subsequent study showed that the PLL linker can be also used to prepare titanium dioxide nanoparticles (TiO 2 NPs) conjugated with DNA. This nanocarrier works by entering and targeting the 3′-noncoding area of the influenza A virus. 113 GFMs can additionally advance development within the field of COVID-19 nanotherapies. Graphene quantum dots (GQD) can deliver drugs and inhibit a virus by target-specific interactions. A recent study involving GQD conjugated with non-nucleoside reverse transcriptase inhibitors (NNRTI) showed extraordinary anti-HIV activity with IC50 of 0.09 μg mL −1 . 114 In another study, graphene oxide modified with nano-Ag (GO-Ag nanocomposite) was developed for the reduction of viability of porcine reproductive and respiratory syndrome virus (PRRSV) and epidemic diarrhea (PEDV). Obtained results showed that the GO-Ag nanocomposite was more beneficial compared to nano-Ag and GO alone. 115 It prevented entering viruses into hosts and enhanced expression of interferon (IFN)and interferon-α (IFN-α)-stimulating genes. Other nanotechnological solutions include polymeric NPs as capping agents for the delivery of antiviral agents. Polymeric nanostructures offer feasible synthetic protocols, very low cytotoxicity, and good biocompatibility. Recent examples under preclinical trials include siRNA-loaded nanostructures based on "STP702" (Fluquit) for the delivery and targeting of avian flu (H5N1), swine flu (H1N1), and H7N9 viruses. 116 Involvement of the "ALN-RSV01" targeting agent allowed direct binding with nucleocapsid "N" genes of respiratory syncytial virus (RSV). 117 The RSV virus can be also inactivated using virus-like NPs, delivering the fusion proteins (F VLP) which induce killer T-cells naturally present in patients' lungs. 118 The polylactide nanostructures are also advantageous for delivery of antiviral agents. The biodegradable synthetic polylactic-coglycolic acid (PLGA) is already approved by the United States Food and Drug Administration (FDA) for medicinal applications and can be further successfully used. 119 Peptide-based NPs are also interesting candidates for antiviral nanomedicinal applications such as short-sequenced inhibitors that cause mutations within virus replication. 120 Studies based on recent findings on formation of intracellular virus-induced cytosolic double-membrane vesicles 45 may also provide a breakthrough in development of antiviral nanodrugs. Smart NPs after entering the host cells may target and subsequently block the function of crown-shaped pores. This will prevent transportation of the transcripted RNA outside the vesicles and further RNA translation. Virus Prevention and Treatment by Using Nanomaterials with Mixed Mechanisms of Action. At the beginning, it is noted that dimensions of most types of nanomaterials are too large to be internalized into the viral capsid. Also, viruses do not express specific self-internalization mechanisms. Therefore, smart nanomaterials can mostly interact with external capsid machinery. A recent study thoroughly describes the structural elements of the SARS-CoV-2 virus. 121 On the basis of this knowledge, we name the potential targets for smart antiviral hybrid-structured nanotechnological solutions with mixed specific and nonspecific mechanisms of action (Figure 1a ). While considering nanomaterial dimensionality, it may first block the action of spike-family proteins such as S1 and S2 subunit functionals and other S glycoproteins. Subsequently, the nanomaterial can disturb the functioning of the membrane (M), envelope (E), and accessory (e.g., ORF7a) proteins. In the case of too large platform dimensionality or specific multifunctionality, the nanomaterial can additionally release ions or various therapeutic agents to travel through the envelope and target the internal protein machinery. Herein, it can disturb the group of various functional proteases such as pappain-like (NSP3) and main (NSP5) proteases, RNA replicase (NSP9), helicase (NSP13), as well as NSP 7, 8, 10, 12, and 15. Moreover, it may block the entry complex formation by releasing inhibitors of ACE2 and/or TMPRSS2 receptors. If the first gatekeeper is broken and the virion enters the host, the nanomaterial can already be there as a result of safe internalization. After stimuli−response decomposition, it releases the second line of defense inside the host. The group of corresponding targets is presented in Figure 1b . The expected effect may cause the disturbance of virion endosomal acidification (in case of endocytosis), uncoating of RNA, formation of intracellular vesicles for RNA transcription, blocking of the corresponding crown-shape transportation pores and replication complexes formation (transcription and translation of RNA by host machinery), packaging of new virions (RNA coating and composing the proteins), and exocytosis of new virions (viral daughter particles). The important step that can be targeted with smart antiviral nanomaterials with nonspecific action is the viral action inside the host. Preliminary investigations suggested that after SARS-CoV-2 entry, the viral capsid solubilize, and uncoated nucleocapsid proteins release the RNA directly into the host cytoplasm. 24 However, more deep studies using cellular electron cryo-microscopy (cryo-EM) have shown that after entry SARS-CoV-2 induces formation of cytosolic double-membrane vesicles. 45 Subsequently, they provide a unique microenvironment for RNA replication, while further replication stages involve helicase and RNA polymerases (RdRP). It was previously shown that many viruses induce complex membrane rearrangements to optimize and maximize RNA replication and transcription and thus protect the machinery against the host ACS Sustainable Chemistry & Engineering pubs.acs.org/journal/ascecg Perspective cell defense. These rearrangements are probably connected to the autophagic mechanism of action because they possess the morphotype of endoplasmic reticulum (ER) invagination or extrusion. 122 It was also found that these small doublemembrane vesicles are additionally armed with specific crownshape molecular pore complexes. 45 By using these pores, newly synthesized RNA can travel outside vesicles into the host cytoplasm. Therefore, it becomes clear that blocking the release of replicated RNA by a smart antiviral nanotherapeutic may be an efficient way for halting virus development inside infected cells. Afterward, virion development stages can be also targeted using nanomaterials. These include viral proteins that are further translated inside the host and are proteolytically processed by the precise work of chymotrypsin-like and papain-like proteases. If this machinery exhibits any weak points connected with a unique expression of specific molecules, they may be also used for easy targeting with nanomaterials. After every construction element is ready, the new virion is assembled and released from the host into the exocytic system. 123 Even if this journey appears unfinished, new virions may be already damaged by nanomaterials while showing less infectivity. Also, there are many variations of possible combinations of components that can be used for development of smart antiviral nanomaterials. They are schematically envisioned in Figure 2 . Such multicomponent multifunctional hybrids can be designed by using both organic functionalities and inorganic nanocompartments. The base for the bottom-up construction is the so-called nanoplatform. It can be designed using spherical or 2D materials and further build up with other nano/bioagents to achieve each particular effect such as targeting, responsive delivery, therapy, imaging, toxicity diminishing, and stealthing nanoconstruction elements. If rationally planned and thoroughly verified, multicomponent multifunctional antiviral nanomaterials can offer the ideal combination of functionalities. As a result, the mixed specific and nonspecific mechanisms of action will allow achieving the most desirable nanotherapeutic effects, as presented in Figure 1 . Viruses along with living organisms are subject to evolutionary selection processes. Their characteristic feature is the high frequency of spontaneous mutations, ensuring the development of resistance to almost any stress or impact. SARS-CoV-2 is an RNA-containing virus. This type has an order of magnitude higher mutation rate compared to DNAcontaining ones. 124 However, the SARS-CoV-2 virus has an unsegmented genome, which excludes variability as a result of gene reassortment. To date, existing data on resistance of the SARS-CoV to various disinfectants revealed susceptibility to commonly used substances 125 for which SARS-CoV-2 is sensitive as well. 126 The use of nanomaterials as antiviral agents is based on certain physicochemical properties that allow them to interact directly with viral particles (interference with receptor interaction or viral absorption) or to exert an effect through intermediate mechanisms (for instance, generation of ROS). Nanosized particles used as carriers for conventional antiviral drugs stays, however, outside of the framework of this paragraph. In the framework of hypothesized considerations, inorganic nanomaterials can be arranged in order of probability of resistance development. Most likely, the resistance of the viral population could be developed to various absorbers. The idea underlying the concept of nanodisinfectants is the inactivation of viral particles due to absorption before they enter the cell. The driver of this process is the electrostatic interaction between positively charged viral proteins and nanomaterial, such as GO. 56 Likely, a point substitution in the amino acid sequence of viral proteins will change the total net charge of the viral particle, leveling the factor of electrostatic or hydrophobic interaction. In the same way, bacterial cells become resistant to various cationic antimicrobial peptides. 127 Another way to prevent virus entry is to interfere with receptor interactions between the virus and the cell. It was found in experiments in vitro that metal NPs such as zinc oxide or surface-modified Au NPs have binding affinity to viral glycoproteins. 128 Ag NPs can directly bind to HIV-1 gp120 glycoprotein knobs. 129 A possible mechanism of resistance, in this case, may be associated with point changes in the composition of the glycoprotein due to mutation. In clinical practice, there is only one drug that interferes with receptor interactions"Enfuvirtide", which is 36 amino acid peptide that binds to the gp41 domain of the HIV-1 envelope inhibiting viral entry into cells. 130 To date, resistant forms of HIV have already been registered, which have mutations altering co-receptor tropism, co-receptor affinity, or fusion kinetics. 131 Certain nanomaterials (fullerenes, graphene) can produce ROS under irradiation, which decompose the viral genetic material, lipids, and proteins. 132 Similarly, ROS kills various microorganisms. However, unlike bacteria, 133 viruses do not have genes encoding appropriated enzymes. Nevertheless, in 2012, a case of virus resistance to oxidative stress due to enzymatic inactivation was found. 134 HSV-1 herpes simplex virus was observed to be somewhat resistant to inactivation by hydrogen peroxide, and it was found that catalase was located inside the HSV-1 envelope. The authors suggested that catalase was incorporated into the viral envelope during HSV-1 virion assembling. An important factor contributing to the emergence of resistant forms along with the mutation rate is the virion's productivity. Maintaining a low level of production of new virions is a key point in the treatment of viral infections. 135 However, it has been relatively recently discovered that viruses follow yet another survival strategy referred to by authors as "drug tolerance by synchronization". 136 It consists of synchronizing the life cycle of the viral population with a drug therapy model, which allows the virus to replicate only when the concentration of the therapeutic agent is low. Thus, antiviral As a consequence, inorganic nanomaterials used as disinfectants and protection leave a little chance for viruses to survive and getting into the host. Nevertheless, the right way is to combine several nanomaterials with different mechanisms of action or targets in one formulation or nanohybrid system, which significantly reduce the probability of resistance development. Today, as we know, no cases of the emergence of viral resistance to treatment with nanomaterials have been identified. Therefore, developed antivirals that involve nanomaterials can be assumed as presumably safe in terms of potential viral resistance. EQUIPMENT It is accepted that COVID-19 patients suffer from a wide range of different symptoms or mostly are the silent carriers of SARS-CoV-2. So far, no fully effective antiviral treatment is available against COVID-19. Therefore, the person-to-person transmission of SARS-CoV-2 is a large problem that needs to be solved not only during this pandemic period but also beyond it. It is obvious that if the virus-carrying person while coughing or sneezing rapidly spread infected saliva droplets into the air. Droplets that dissolve and form aerosols are subsequently suspended in the air for a long period and can travel long distances through the air. 15 At a first glance, keeping a minimum of 2 m of distance between infected people can be beneficial; however, droplets may still remain on surrounding surfaces. When virions persist on surfaces, they lead to surface-related person-to-person transmission. Virions sizes, which range from 10 nm to 6 μm, 137 allow them to be aspirated into lungs and settle on the surface of bronchia or even alveoli. It is accepted that wearing masks can reduce both the spreading and respiration of aerosol particles. However, bearing in mind virus particle sizes, it is questionable if masks composed of only fabric allow for an acceptable protection level. A recent study investigated the aerosol filtration efficiency of a variety of synthetic and natural fabrics including cotton, silk, polyester, flannel, and chiffon. 137 As expected, the size and amount of particles that remained in the air after passing through the fabric varied significantly. A single layer of high thread count cotton cuts off around 80% for particles over 300 nm. A combination of layers of fabrics (for instance, one cotton layer plus two silk layers) gave better results (with over 90% cut off efficiency) probably because of differences in electrostatic properties of different fabrics and a large final thickness. It was also noted that professional masks can block the virus but do not deactivate it which may still cause infective transmission. Therefore, a nanomaterial-based protective coating on fabric masks is needed to decrease the threat of infection. 138 Also, other types of protective equipment can benefit from nanotechnology-based protective coatings. The first approach considered a biocidal nanosilver for coating surgical masks. 139 The photocatalytic TiO 2 -based nanostructures can be also used to adsorb SARS-CoV-2 virions from the air and further deactivate them by using UV light. 140 Other approaches can also take advantage of low virus survival when placed on a copper surface. 19 Antiviral nanocoatings can be painted or sprayed on surfaces and may include silver, titanium dioxide, or copper NPs which will allow for strong blocking effects toward virus activity. The coatings may be dispersed over surfaces with aerosol or incorporated into paints that will enable the controlled release of metal ions from the surface. 141 Recent advances also include nanoabsorbents that could deactivate the SARS-CoV-2 virus. 142 Smart solutions designed for surface protection (including masks) can be also based on a mixture of different NPs such as halloysite nanoplates, nanosilver, nanozinc oxide, and nanotitanium dioxide. Therefore, a considered mechanism is based on the visible-light-driven photocatalytic function of the nanomaterials' blend which requires the presence of light for activation of photocatalytic action. 143 On the other hand, in very dark indoor or outdoor conditions, nanomaterials are set to a standby state. Therefore, apart from composing the in-house simple mixtures of different NPs, the advanced nanotechnological solutions may include more hybrid types of nanostructures with unique and exciting biocidal action. The considered nanosolutions for the manufacturing of innovative personal protective equipment (including face masks) may further include 2D materials. 87 Due to large recognizability, the first proposed solution involved graphene and its related materials. Graphene-based face masks offer features such as washability, reusability, and antistatic properties (repelling airborne particles), as well as bacteria and virus resistance. 144 Commercially available surgical masks can be functionalized with few-layer graphene by a dual-mode laser-induced forward transfer technique. These masks possessed outstanding superhydrophobic, self-cleaning, and photothermal properties under sunlight illumination. 145 Other solutions include nanographene applied in the form of paints and varnishes to walls and surfaces of public settings that are high-risk areas for micro-organisms such as bacteria and viruses, including shopping malls, metro stations, airports, and event halls. These solutions feature the UV curability of the coating and a no-color formula. 146 It should be noted that a large potential in pathogen elimination also comes from other interesting and diverse 2D structures. There is no doubt that preventative actions in public and healthcare settings are of critical importance. Many researchers have recently turned their focus toward the problem of infection prevention, and a global effort is underway to minimize the spreading of SARS-CoV-2 and to protect healthcare professionals who are on the front lines of the pandemic, as well as people's everyday activities. Rapid verification of the efficiency of these nanotechnological solutions toward the native SARS-CoV-2 virus is needed, as well as confirming their safety. The COVID-19 pandemic has raised doubts that in the postpandemic scenery sustainability will be pushed into the sidelines. The need for fast rebuilding the global economy may slow down implementation of more environmentally friendly solutions. The unprecedented health and economic crisis may, however, paradoxically force the world to revisit the green order. This can be done by using the 12 principles of green engineering, which were here adopted with minor changes from Anastas and Zimmermann et al. 38 The principles decompose the general rule into functional pieces, in terms of products, processes, and systems, which allow maximizing sustainability in a globally understood fashion. These principles were herein adjusted for designing nanotechnological solutions and were schematically presented in Figure 3 . They can be used as guidelines or a ACS Sustainable Chemistry & Engineering pubs.acs.org/journal/ascecg Perspective checklist for development of more green nanomaterials. It is also noted that the principles correlate with the circle of sustainable development, presented in Figure 4 . It divides the required features into three parts such as consumer demand, industry offer, and product end of use. In this context, the development of smart solutions against the COVID-19 pandemic is considered the unprecedented opportunity only if both the 12 principles and the cycle of sustainable development are preserved. Nanotechnology can undoubtedly enable the rapid elimination of SARS-CoV-2 damage to public health. However, this investment needs to enable achieving global sustainability goals. In this context, it is important to search for solutions that significantly and positively support sustainability. 147 Therefore, developed nanotechnological solutions must be even more intelligent, for instance, not only in terms of increasing the protective and treatment efficiency but also in minimizing potential hazards and postprocessing effects. 148 Developed nanotechnologies should be responsible. This means in regard to nanotechnological safety regulations mentioned, for instance, in "Nanosafety in Europe 2015− 2025: Toward Safe and Sustainable Nanomaterials and Nanotechnology Innovations", 149 as well as conclusions of the "2019 Global Summit on Regulatory Science" (GSRS19, 2019, Sept. 24−26), hosted by the European Commission's Joint Research Center (JRC) and U.S. National Nanotechnology Initiative (NNI). 150 New nanotechnological solutions should care about a reduction of waste. The so-called E-Factor should be lowered as should toxic and potentially toxic reagents or intermediates that can harm humans and the environment. This applies to the entire production chain. 151 In this aspect, it is suggested to replace toxic reagents with more environmentally friendly ones if can deliver equally good results. It was previously noted that virucidal hybrid-structured nanomaterials need high complexity to be efficient and smart. In this context, principle 9 of the 12 principles of green engineering needs further discussion. In general, it states that material diversity can be minimized in multicomponent products. This should be, however, considered only if they do not provide significant added value such as emerging multi- ACS Sustainable Chemistry & Engineering pubs.acs.org/journal/ascecg Perspective functional antiviral nanoplatforms, which can be designed by using nano-modifying agents of natural origin. Inorganic nanocomponents are already used to produce intelligent antiviral agents, but they mostly lack sustainability in general terms. Given graphene oxide as an example, it is highly recommended to produce it by electrochemical techniques. 152 These, compared to the commonly used Hummers method, limit the use of harmful acids (potassium permanganate, concentrated sodium nitrate, and sulfuric acids) and waste in the form of water which is commonly used to rinse the final product. It is also important to reduce these nonsustainable stages to the necessary minimum. When considering the promising MXene materials, their synthesis techniques also have a lot of room for improvement in the aspect of sustainability. At the initial stage, hydrofluoric acid (HF) and delamination were commonly used in highly toxic mixtures of tetramethylammonium hydroxide (TMAOH) or tetrabutylammonium hydroxide (TBAOH). 153 These solutions were recently replaced by a technique in which HF is formed in situ in a LiF/HCl mixture together with confirmation of the scalability. 154 While the technology is based on strong acid reagents and the final product requires numerous washes, researchers put an effort to increase the sustainability added value by including natural reagents and antioxidants such as Lascorbic acid, which is commonly known as vitamin C. 155 This is a good direction for oxidation stability enhancement that can be truly considered as both effective and sustainable. Developed nanomaterials also require detailed instrumental characterization. Intensive data analysis helps in understanding the biological properties and mechanisms of action. The issues of cytotoxicity and ecotoxicity of the antiviral nanomaterials are crucially important in the aspect of sustainability. In other words, it is important to thoroughly characterize nanomaterials to enable assessment of their impact on end-user health and the environment. It is worth searching for more safe and sustainable approaches. Already known nanomaterials can be synthesized using green methods. The best example here is nanosilver. Silver ions can be reduced to metallic nanoparticles using natural antioxidants and biologically derived extracts. 46 Developed synthesis techniques should, wherever possible, use green replacements for raw materials, greener processes, renewable energy, reused solvents, and other features with reduced impact on the planet and its resources. The development of modern therapeutic compounds and nanomaterials for use in medicine involves the selection of expensive ingredients and reagents of high purity that are produced with low yield and then repeatedly purified in processes generating large amounts of waste. The high prices of nanotechnologies and nanoproducts developed in this way limit their availability, which not only does not go with the spirit of sustainable development but is also simply not ecological. Sustainable development can be successfully implemented around smart solutions for nanomedicine in the aspect of combating the SARS-CoV-2 virus. Such solutions should be developed from the very beginning following the principles of green chemistry. In this regard, technological processes and stages should be simplified and/or optimized. For each antiviral nanoproduct, the life cycle analysis should be performed. Such analysis considers resources, processes, and product use/ deposition/reuse. In this aspect, it is encouraged to use quantitative metrics to characterize improvements in sustainability. When designing new effective nanotherapeutics, it is important to achieve maximum efficiency in delivering the active substance with a minimal concentration in the body. This is important for not only the choice of a therapeutic substance and method of therapy but also the carrier, which is specially designed to precisely release the substance on demand. Innovative systems of targeted drug delivery should be characterized by high selectivity. Materials used in drug delivery and so-called building blocks in the development of intelligent antiviral drug delivery platforms should work on demand and in place. In parallel, increasing emphasis is placed on fighting the SARS-CoV-2 virus using more safe and sustainable solutions. It is accepted that new therapies and used materials are cost generating regarding synthesis, biological research, and preclinical and clinical trials. Nevertheless, biobased materials can be also used such as chitosan and cellulose, as well as biodegradable polymers, and nanomaterials. In other words, antiviral NPs should pose no environmental problems when released in the process of recycling or biodegradation. Instead, they should be disintegrated efficiently in the natural environment. For the case of protective equipment, if antiviral masks are produced, they should be based on natural raw materials and biodegradable polymers. In the situation of such widespread use of plastic masks, recycling poses a huge challenge. In the worstcase scenario, the materials used should be at least recyclable or reused. A good example is the recently reported possibility of reusing face masks and personal protective equipment from the healthcare professionals. 156 The scientific community can contribute greatly to battle the COVID-19 pandemic. Our best weapon here is research and development involving advanced nanotechnological solutions. By design, hybrid nanostructures can express a unique combination of mechanisms of antiviral action. However, these mechanisms need to be revisited to enable more rational development of the new generation of antiviral nanomaterials. As an exclusive outlook, we verify and categorize the potential antiviral effects into three modes of action that can be developed for nanomaterials and smartly managed against the SARS-CoV-2 virus. The first type refers to the specific mechanism of nanomaterials action. This is the case when nanomaterial mostly reversibly targets receptors or ligands on the surface of the virus or cell that leads to the prevention of virus−cell interaction. The second type is the nonspecific action, which has a destructive effect on various structures of the virion regardless of their taxonomic position. Their action is not guided and leads to irreversible deactivation of the virus, also upon dilution. The third group concerns mixed-type antivirals. They provide complex bioeffects that are challenging to understand and control. On the other hand, they can be smartly tailored for the on-demand and/or stimuli−response manner of action. To make the right choice on the needed mechanism, it is important to analyze the antiviral efficiency against a minimum of two types of viruses, for example, enveloped and nonenveloped. If the nanomaterial exhibits intensified action within the specific site of the chosen in vitro and/or in vivo model, it becomes clear that it is intentionally or nonintentionally guided. The locations of the reaction site and key nanomaterial functionalities need to be elucidated. Finally, it is equally ACS Sustainable Chemistry & Engineering pubs.acs.org/journal/ascecg Perspective important to verify the antiviral efficiency upon dilution and/or upon losing nanomaterial−virus interaction. Below, we envision target hot points, concerning the action of smart hybrid-structured antivirals with mixed mechanisms of antiviral action that may efficiently halt the SARS-CoV-2 virus morphology and life cycle inside the host cell. For the case of infection (entry) prevention, the nanoparticulate antiviral system should work effectively outside the host cells, not allowing virions to introduce their genetic material inside them. Here, the relatively limited range of different effects can be used toward formation of the viral−host entry complex. The expected effects may include damage of the following: (1) viral envelope and membrane proteins (2) viral spike glycoproteins, disturbing their key infective action toward human host ACE2 and TMPRSS2 (3) viral NSP-family proteases, disturbing their further action (4) nucleocapsid proteins, enclosing viral RNA (5) nucleic acids, forming sRNA fragments As can be seen, the target is the disturbance of the starting point of the viral life cycle, i.e., the entry step. This can be done by blocking the viral−host membrane fusion or endocytosis by the host cell. For the case of infection treatment, the nanodrug should first enter the host cell and work specifically in its interior to target the stages of viral action. Here, a wide range of different effects can be activated. The target effect may cause disturbance of the following: (1) acidification and solubilization of formed endosomes (2) uncoating of the sRNA (3) inhibition of intracellular cytosolic double-membrane vesicles formation (for RNA replication) (4) blocking crown-shape pores embedded in cytosolic vesicles (for transportation of RNA outside the vesicles) (5) inhibition of replication complexes formation (disturbing transcription and translation of RNA by host machinery) (6) packaging and assembly of new virions (RNA coating and composing the protein scheme) (7) exocytosis and release of new virions (viral daughter particles) The final expected outcome is a disturbance that causes blocking or significantly slowing the viral life cycle after host cell entry. This is important for replication and propagation steps. The inhibition of formation and/or secretion of viral daughter particles is needed. If they are released, however, their function should be highly damaged causing them to be out of order or possessing significantly lower infectivity. When designing effective antiviral nanosystems, one can notice that many features of the material are verified and controlled. The reason is that the above-mentioned effects may correspond to direct physical and/or chemical interactions, as well as expressing the targeting agents, and the release of virucidal agents, ions, individual NPs, or reactive oxygen species. To the best of our knowledge, the material features to be assessed and controlled include the presence of metallic nanocomponents, ceramic−nanocomponents, and organic stabilizing agents and/or a solid envelope and also their size, shape, surface area, chemical composition, solubility, colloidal features (including hydrodynamic diameter and zeta potential), corresponding red−ox properties, and ROS scavenging features. It should be additionally noted that the specific viral response to bioactive nanosystems (adaptation by mutations, resistance development) is not expected because virions are not considered as living organisms, and their changes are only associated with RNA replication cycles. It can be also assumed that if a complicated enough nanosystem is designed, it can generate some synergistic and/or additional biological effects not yet observed for enveloped viruses. Also, the issue of the lack of stability of viral features is a major concern. Viruses are changing themselves (rapidly or slowly mutating), and they are constantly moving (around the cells and crossing their membranes). Developed nanomaterials need to be smart to face the corresponding pipelines. For this purpose, multiple functionalization strategies are needed. Developed nanodrugs need to provide effective, as requested, stepwise virucidal action. The positive effects need to be amplified, and virus particles should be targeted just before the creation of entry complexes to provide maximum protection of healthy cells. In this regard, minimization of disease symptoms (cytokine storm, among others) is highly requested. After performing their duty, developed nanomaterials should subsequently decompose and solubilize to nontoxic removable products. The on-site toxicity, as well as acute and chronic off-target responses, must be carefully investigated to ensure maximum safety. Therefore, another aspect of the use of nanomaterials as virucidal agents is their biosafety. Nanomaterials can be used to inactivate the virus outside the cells (host) and as carriers for antiviral drugs into the cells. In the first case, this is a relatively more safe way to inactivate viruses, while the use of nanomaterials (especially inorganic NPs) for introduction into the body can have negative consequences, which, on the one hand, can be remote in time, and, on the other hand, can complicate the course of viral infection in the current moment. In general, research works suggesting the use of inorganic nanomaterials as antiviral agents are based on the results of toxicity tests performed on various cell lines. 128 It is worth noting that under in vitro conditions numerous NPs are recognized as low toxic. Often, the scope of such works is not related to a comprehensive study of the biosafety of NPs following relevant regulations. Moreover, only relatively recently the development of such regulations has become the subject of efforts of the scientific community. 157 Significant coordinated efforts are underway to harmonize existing hazard and risk assessment methods in the framework of the NANoREG project. 157 The main points that will have to be encountered in the certification of nanomaterials for nonmedical purposes can be identified when studying guidance developed by The Scientific Committee on Consumer Safety (SCCS). 158 This guidance requires a thorough safety assessment of nanomaterials in the same way as other chemicals but with special attention to their extremely small size. Due to the fact, that SARS-CoV-2 directly attacks lung cells, development of NPs-based inhalation-administered drugs against the virus was recently suggested with argumentation on systemic inactivation of the virus. 28 The state-of-the-art studies, however, do not fully support the probability of success in this area because of possible detrimental health effects. This subject was comprehensively reviewed by Nho. 159 The lungs are very sensitive organs that if constantly exposed to nanobased drugs with long-term repeated dose will inevitably cause accumulation of nanomaterials in lung tissues, resulting in inflammation, systemic circulation, and finally lung tissue injury. Also, a post-inhalation cough can appear after using therapeutic aerosols. 160 This is a result of lung inflammation and increased hypersensitivity and/or changes in the epithelial lining fluid composition. In the frame of the recently assessed influence of ACS Sustainable Chemistry & Engineering pubs.acs.org/journal/ascecg Perspective SARS-CoV-2 on the appearance of a cytokine storm, 110 the additive inflammation by the presence of nanomaterials can cause catastrophically synergistic inflammation effects. As can be seen, the administration of nanomaterial-based drugs needs to be carefully investigated in long-term exposure aspects if administered into the lungs. On the other hand, several solutions can be effective in cytotoxicity mitigation. This can be done by using stable nanocomposite structure (solid connection/interface) between nano-counterparts 161, 70, 151 or by designing hybrids of 2D material and inorganic nanoparticles (including ceramic and/ or metallic), as well as different organic moieties. The certification process of nanomaterials for drug delivery and cosmetic products takes a long time and assumes that a nanomaterial meets several requirements. Toxicology research planning involves a thorough physical and chemical characterization of NPs. The main emphasis in assessing the hazard class should be placed on determining the parameters: absorption, distribution, metabolism, excretion. It is also important to determine the systemic availability of nanomaterial if it does not have systemic availability, then it is necessary to obtain information on local toxicity and genotoxicity. Protective equipment modified with virucidal nanomaterials also needs to be studied for its potential toxicity. Only nontoxic nanomaterials or composite nanostructures with diminished toxicity are the best choices here because they minimize the risk of releasing nanomaterials and express specific types of ionic action instead of direct nanomaterial entry into the cells. Nevertheless, for the case of face masks, the potential inhalation of NPs should be considered, whereas in the case of other types of protective equipment, the lack of potential skin toxicity upon contact needs to be verified. In the next steps toward developing smart nanotechnologies, subsequent scaleup and distribution are needed together with a long-term strategy toward use, life cycle, reuse, deposition, and recycling. Reflecting on a slightly more optimistic summary, it can be assumed that the impact of the COVID-19 pandemic on the economy, population, and planet can have both short-and longterm benefits. The health, social, and economic effects of the crisis require urgent and extraordinary action by businesses and governmental administrations. Many enterprises implemented contingency plans to survive the economic storm, which creates the need for integrated actions around sustainable development. Still, society, the environment, and the economy are the pillars of sustainable development. The need for rapid recovery after a pandemic period imposes the need for rapid development. It would not have been possible without modern technical solutions, among others, based on nanotechnology. This path will be followed by, for example, the European Union, which has the chance to include the Green Deal strategy in the plan of rebuilding the European economy after the coronavirus pandemic. The reconstruction of local and national economies should be based on a circular model. This is strictly linked to issues related to strategic raw materials, environmental protection, and energy independence. Therefore, sustainable development assumptions can be effectively implemented using smart nanotechnological solutions. In this regard, only a fast track to the market will enable maximization of the response toward COVID- 19 ■ REFERENCES WHO resources WHO Novel Coronavirus (2019-nCoV) situation reports Animal Coronaviruses: Lessons for SARS Insights into the cross-species evolution of 2019 novel coronavirus Novel coronavirus disease (COVID-19): a pandemic (epidemiology, pathogenesis and potential therapeutics) Phylogeny of SARS-like betacoronaviruses including novel coronavirus from Wuhan using data generated by the Shanghai Public Health Clinical Center & School of Public Health, the National Institute for Viral Disease Control and Prevention, the Institute of Pathogen Biology, and the Wuhan Institute of Virology shared via GISAID A pneumonia outbreak associated with a new coronavirus of probable bat origin Rapid repurposing of drugs for COVID-19 Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination Severe acute respiratory syndrome coronavirus on hospital surfaces Aerosol and surface distribution of severe acute respiratory syndrome coronavirus 2 in hospital wards Survival Characteristics of Airborne Human Coronavirus 229E Humidity is a consistent climatic factor contributing to SARS-CoV-2 transmission Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1 School of Public Health resources Association of COVID-19 transmission with temperature or UV radiation in Chinese cities Inactivation of the coronavirus that induces severe acute respiratory syndrome, SARS-CoV Nanotechnology-based disinfectants and sensors for SARS-CoV-2 Molecular immune pathogenesis and diagnosis of COVID-19 Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review Revisiting the cytotoxicity of quantum dots: An in-depth overview Antimicrobial Nanomaterials and Coatings: Current Mechanisms and Future Perspectives to Control the Spread of Viruses Including SARS-CoV-2 Toward Nanotechnology-Enabled Approaches against the COVID-19 pandemic Nanotechnology for COVID-19: Therapeutics and Vaccine Research Opportunities and Challenges for Biosensors and Nanoscale Analytical Tools for Pandemics: COVID-19 Fighting COVID-19: Integrated Micro-and Nanosystems for Viral Infection Diagnostics Can Nanotechnology and Materials Science Help the Fight against SARS-CoV-2? On Facing the SARS-CoV-2 (COVID-19) with Combination of Nanomaterials and Medicine: Possible Strategies and First Challenges COVID-19: Progress in diagnostics, therapy and vaccination Detecting the Coronavirus (COVID-19) Challenges in Laboratory Diagnosis of the Novel Coronavirus SARS-CoV-2 COVID-19 vaccines: Knowing the unknown Design Through the 12 Advancing the Use of Sustainability Metrics Advancing the Use of Sustainability Metrics in ACS Sustainable Chemistry & Engineering Plectranthus amboinicus-mediated silver, gold, and silver-gold nanoparticles: phyto-synthetic, catalytic, and antibacterial studies Sustainable self-assembly strategies for emerging nanomaterials Substrate specificity profiling of SARS-CoV-2 Mpro provides basis for anti-COVID-19 drug design Activity profiling of SARS-CoV-2-PLpro protease provides structural framework for anti-COVID-19 drug design A molecular pore spans the double membrane of the coronavirus replication organelle Antiviral activity of mycosynthesized silver nanoparticles against herpes simplex virus and human parainfluenza virus type 3 Glutathione-Stabilized Fluorescent Gold Nanoclusters Vary in Their Influences on the Proliferation of Pseudorabies Virus and Porcine Reproductive and Respiratory Syndrome Virus Inhibition of HSV-1 attachment, entry, and cellto-cell spread by functionalized multivalent gold nanoparticles Novel antiviral characteristics of nanosized copper (I) iodide particles showing inactivation activity against 2009 pandemic H1N1 influenza virus Tin oxide nanowires suppress herpes simplex virus-1 entry and cell-to-cell membrane fusion Prophylactic, therapeutic and neutralizing effects of zinc oxide tetrapod structures against herpes simplex virus type-2 infection Photocatalytic inactivation of viruses using titanium dioxide nanoparticles and low-pressure UV light Functional Carbon Quantum Dots as Medical Countermeasures to Human Coronavirus Design of boronic acid-attributed carbon dots on inhibits HIV-1 entry Antiviral Activity of Graphene Oxide: How Sharp Edged Structure and Charge Matter Antiseptic properties of two calix[4]arenes derivatives on the human coronavirus 229E Sialylneolacto-N-tetraose c (LSTc)-bearing liposomal decoys capture influenza A virus Silver Nanoparticle Based Codelivery of Oseltamivir to Inhibit the Activity of the H1N1 Influenza Virus through ROS-Mediated Signaling Pathways Nanoscale nights of COVID-19 Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism A crucial role of ACS Sustainable Chemistry & Engineering pubs angiotensin converting enzyme 2 (ACE2) in SARS coronavirusinduced lung injury SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Different host cell proteases activate the SARScoronavirus spike-protein for cell-cell and virus-cell fusion Functional balance between haemagglutinin and neuraminidase in influenza virus infections Global Transmission of Oseltamivir-Resistant Influenza Considerations around the SARS-CoV-2 Spike Protein with Particular Attention SARS-CoV-2 spike protein: an optimal immunological target for vaccines Recent advances in graphene family materials toxicity investigations Nanosheets of oxides and hydroxides: Ultimate 2D charge-bearing functional crystallites 2D transition metal dichalcogenide nanomaterials: advances, opportunities, and challenges in multifunctional polymer nanocomposites The twodimensional phase of boron nitride: Few-atomic-layer sheets and suspended membranes Graphene-analogous low-dimensional materials Buckled two-dimensional Xene sheets Two-dimensional nanocrystals produced by exfoliation of Ti3AlC2 Surface interactions between 2D Ti3C2/Ti2C MXenes and lysozyme MXene) as a novel highly efficient and selective agent for photothermal therapy Adsorptive environmental applications of MXene nanomaterials: a review Antibacterial Activity of Ti3C2Tx MXene Biological Activity and Bio-Sorption Properties of the Ti2C Studied by Means of Zeta Potential and SEM Antimicrobial Mode-of-Action of Colloidal Ti3C2Tx MXene Nanosheets The Atomic Structure of Ti2C and Ti3C2MXenes is Responsible for Their Antibacterial Activity Toward E. coli Bacteria Two-dimensional nanomaterials beyond graphene for antibacterial applications: current progress and future perspectives Can graphene take part in the fight against COVID-19? The Impact of Zeta Potential and Physicochemical Properties of TiO2-Based Nanocomposites on Their Biological Activity Influence of bacteria adsorption on zeta potential of Al2O3 and Al2O3/ Ag nanoparticles in electrolyte and drinking water environment studied by means of zeta potential Bacterial Adsorption with Graphene Family Materials Compared to NanoAlumina Synthesis of the RGO/Al2O3 core−shell nanocomposite flakes and characterization of their unique electrostatic properties using zeta potential measurements Synthesis of RGO/TiO2 nanocomposite flakes and characterization of their unique electrostatic properties using zeta potential measurements Cellular uptake of nanoparticles as determined by particle properties, experimental conditions, and cell type Coronavirus envelope protein: current knowledge Graphene oxide and lipid membranes: interactions and nanocomposite structures Virus capture and destruction by label-free graphene oxide for detection and disinfection applications Integration of reverse transcriptase loop-mediated isothermal amplification with an immunochromatographic strip on a centrifugal microdevice for influenza A virus identification The role of nanotechnology in the treatment of viral infections Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro Strategies in the design of nanoparticles for therapeutic applications Nanotechnology and the treatment of HIV infection Nanoparticles: cellular uptake and cytotoxicity Engineering of 2D Ti3C2MXene Surface Charge and its Influence on Biological Properties Juggling Surface Charges of 2D Niobium Carbide MXenes for a Reactive Oxygen Species Scavenging and Effective Targeting of the Malignant Melanoma Cell Cycle into Programmed Cell Death A simple, low-cost and green method for controlling the cytotoxicity of MXenes Glycyrrhizic-Acid-Based Carbon Dots with High Antiviral Activity by Multisite Inhibition Mechanisms Multisite Inhibitors for Enteric Coronavirus: Antiviral Cationic Carbon Dots Based on Curcumin Sustainable Nanosheet Antioxidants for Sepsis Therapy via Scavenging Intracellular Reactive Oxygen and Nitrogen Species COVID-19: consider cytokine storm syndromes and immunosuppression Novel Gold Nanorod-Based HR1 Peptide Inhibitor for Middle East Respiratory Syndrome Coronavirus Nanoparticle-Mediated Nonviral DNA Delivery for Effective Inhibition of Influenza a Viruses in Cells MPG-based nanoparticle: An efficient delivery system for enhancing the potency of DNA vaccine expressing HPV16E7 Graphene Quantum Dots Based Systems As HIV Inhibitors Antiviral Activity of Graphene Oxide−Silver Nanocomposites by Preventing Viral Entry and Activation of the Antiviral Innate Immune Response Kehn-Hall, K. The use of Nanotrap particles for biodefense and emerging infectious disease diagnostics RNA interference therapy in lung transplant patients infected with respiratory syncytial virus Respiratory syncytial virus-like nanoparticle vaccination induces long-term protection without pulmonary disease by modulating cytokines and T-cells partially through alveolar macrophages Design and characterization of injectable poly(lactic-co-glycolic acid) pastes for sustained and local drug release Molecular modeling and chemical modification for finding peptide inhibitor against severe acute respiratory syndrome coronavirus main proteinase How to Discover Antiviral Drugs Quickly Virus-induced double-membrane vesicles Human Coronavirus: Host-Pathogen Interaction Antiviral drug resistance as an adaptive process Efficacy of various disinfectants against SARS coronavirus WHO resources Bacterial strategies of resistance to antimicrobial peptides Role of Metal and Metal Oxide Nanoparticles as Diagnostic and Therapeutic Tools for Highly Prevalent Viral Infections Interaction of silver nanoparticles with HIV-1 Massively Parallel Profiling of HIV-1 Resistance to the Fusion Inhibitor Enfuvirtide HIV resistance to the fusion inhibitor enfuvirtide: Mechanisms and clinical implications Trends and targets in antiviral phototherapy Mechanisms of group A Streptococcus resistance to reactive oxygen species Internal catalase protects herpes simplex virus from inactivation by hydrogen peroxide General Mechanisms of Antiviral Resistance Life cycle synchronization is a viral drug resistance mechanism Breathable Vapor Toxicant Barriers Based on Multilayer Graphene Oxide Antimicrobial effect of surgical masks coated with nanoparticles Global Times China Reusable and Recyclable Graphene Masks with Outstanding Superhydrophobic and Photothermal Performances Graphene-Based-Coating-With-Anti-Bacterial-and-Anti-Viral-Properties.html Nanotechnology for sustainability: What does nanotechnology offer to assress complex sustainability problems? Ecotoxicological effects of graphene-based materials. 2D Mater European Commission's Science and Knowledge Service The ecotoxicity of graphene family materials: current status, knowledge gaps and future needs Recent Advances in Green, Safe, and Fast Production of Graphene Oxide via Electrochemical Approaches Guidelines for Synthesis and Processing of Two-Dimensional Titanium Carbide (Ti3C2Tx MXene) Scalable Synthesis of Ti3C2Tx MXene Green synthesis of reduced Ti3C2Tx MXene nanosheets with enhanced conductivity, oxidation stability, and SERS activity Reusability Comparison of Melt-Blown vs. Nanofiber Face Mask Filters for Use in the Coronavirus Pandemic Advanced tools for the safety assessment of nanomaterials The European Commission's Science and Knowledge Service Pathological effects of nano-sized particles on the respiratory system Post-inhalation cough with therapeutic aerosols Formulation considerations In vitro assessment of antibacterial properties and cytotoxicity of Al2O3−Ag nanopowders Peptide Nanoparticles as Novel Immunogens: Design and Analysis of a Prototypic Severe Acute Respiratory Syndrome Vaccine Consensus Statement on the Adherence to Clinical and Laboratory Standards Institute (CLSI) Antimicrobial Susceptibility Testing Guidelines (CLSI-2010 and CLSI-2010-update) for Enterobacteriaceae in Clinical Microbiology Laboratories in Taiwan Nanoparticle-Mediated Nonviral DNA Delivery for Effective Inhibition of Influenza a Viruses in Cells Poly(γglutamic acid) nano-particles combined with mucosal influenza virus hemagglutinin vaccine protects against influenza virus infection in mice Conjugating influenza a (H1N1) antigen to n-trimethylaminoethylmethacrylate chitosan nanoparticles improves the immunogenicity of the antigen after nasal administration Chitosan nanoparticle encapsulated hemagglutininsplit influenza virus mucosal vaccine Nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-trimethyl chitosan (TMC) nanoparticulate systems: Preparation and immunogenicity in a mouse model Intranasal delivery of adjuvant-free peptide nanofibers elicits resident CD8(+) T cell responses A novel subnucleocapsid nanoplatform for mucosal vaccination against influenza virus that targets the ectodomain of matrix protein 2 Virus-like particle vaccine induces protective immunity against homologous and heterologous strains of influenza virus Intranasal vaccination with M2e5x virus-like particles induces humoral and cellular immune responses conferring crossprotection against heterosubtypic influenza viruses Multistrain influenza protection induced by a nanoparticulate mucosal immunotherapeutic Comparing the immune response to a novel intranasal nanoparticle PLGA vaccine and a commercial BPI3V vaccine in dairy calves Sustainable Chemistry & Engineering pubs Biodegradable nanoparticle delivery of inactivated swine influenza virus vaccine provides heterologous cell-mediated immune response in pigs Mucosal Immunity and Protective Efficacy of Intranasal Inactivated Influenza Vaccine Is Improved by Chitosan Nanoparticle Delivery in Pigs Virus-like particle vaccine by intranasal vaccination elicits protective immunity against respiratory syncytial viral infection in mice Polymer chemistry influences monocytic uptake of polyanhydride nanospheres Efficacy of mucosal polyanhydride nanovaccine against respiratory syncytial virus infection in the neonatal calf Sub-nucleocapsid nanoparticles: a nasal vaccine against respiratory syncytial virus RSV N-nanorings fused to palivizumab-targeted neutralizing epitope as a nanoparticle RSV vaccine Carbon Dots As Inhibitors Of Virus By Activation Of Type I Interferon Response High Efficiency of Functional Carbon Nanodots as Entry Inhibitors of Herpes Simplex Virus Type 1 Highly Effective and Safe Polymeric Inhibitors of Herpes Simplex Virus in Vitro and in Vivo Therapeutic silencing of HPV 16 E7 by systemic administration of siRNA-neutral DOPC nanoliposome in a murine cervical cancer model with obesity Investigation of the antiviral properties of copper iodide nanoparticles against feline calicivirus Highly Efficient Multivalent 2D Nanosystems for Inhibition of Orthopoxvirus Particles