This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Perspective www.acsnano.org Toward Nanotechnology-Enabled Approaches against the COVID-19 Pandemic Carsten Weiss,*,# Marie Carriere,*,# Laura Fusco,# Ilaria Capua, Jose Angel Regla-Nava, Matteo Pasquali, James A. Scott, Flavia Vitale, Mehmet Altay Unal, Cecilia Mattevi, Davide Bedognetti, Arben Merkoçi, Ennio Tasciotti, Açelya Yilmazer, Yury Gogotsi, Francesco Stellacci, and Lucia Gemma Delogu* Cite This: ACS Nano 2020, 14, 6383−6406 Read Online ACCESS Metrics & More Article Recommendations ABSTRACT: The COVID-19 outbreak has fueled a global demand for effective diagnosis and treatment as well as mitigation of the spread of infection, all through large-scale approaches such as specific alternative antiviral methods and classical disinfection protocols. Based on an abundance of engineered materials identifiable by their useful physicochemical properties through versatile chemical functionalization, nanotechnology offers a number of approaches to cope with this emergency. Here, through a multidisciplinary Perspective encompassing diverse fields such as virology, biology, medicine, engineering, chemistry, materials science, and computational science, we outline how nanotechnology-based strategies can support the fight against COVID-19, as well as infectious diseases in general, including future pandemics. Considering what we know so far about the life cycle of the virus, we envision key steps where nanotechnology could counter the disease. First, nanoparticles (NPs) can offer alternative methods to classical disinfection protocols used in healthcare settings, thanks to their intrinsic antipathogenic properties and/or their ability to inactivate viruses, bacteria, fungi, or yeasts either photothermally or via photocatalysis-induced reactive oxygen species (ROS) generation. Nanotechnology tools to inactivate SARS-CoV-2 in patients could also be explored. In this case, nanomaterials could be used to deliver drugs to the pulmonary system to inhibit interaction between angiotensin-converting enzyme 2 (ACE2) receptors and viral S protein. Moreover, the concept of “nanoimmunity by design” can help us to design materials for immune modulation, either stimulating or suppressing the immune response, which would find applications in the context of vaccine development for SARS-CoV-2 or in counteracting the cytokine storm, respectively. In addition to disease prevention and therapeutic potential, nanotechnology has important roles in diagnostics, with potential to support the development of simple, fast, and cost-effective nanotechnology-based assays to monitor the presence of SARS-CoV-2 and related biomarkers. In summary, nanotechnology is critical in counteracting COVID-19 and will be vital when preparing for future pandemics. COVID-19: SETTING THE SCENE FOR used in different fields, including cancer therapy and NANOTECHNOLOGY regenerative medicine.5,6 However, nanotechnology is not only inspired by virology to develop novel delivery tools but Through millions of years of evolution, viruses have gained a also at the forefront in combatting dangerous viruses. variety of molecular mechanisms for entry into cells; long-term survival within cells; and activation, inhibition, or modification of the host defense mechanisms at all levels.1 Their ability to Nanotechnology is not only inspired by transfer genes with high efficiency inspired the development of virology to develop novel delivery tools noninfectious recombinant viral vectors for gene-therapy but also at the forefront in combatting applications, beginning in 1990.2−4 Efforts were then underway to improve the safety of viral vectors, including developing dangerous viruses. nonviral drug-delivery systems inspired by the natural capabilities of viruses. Researchers in the field of nanomedicine Published: June 10, 2020 have designed a variety of nanosystems that can mimic the gene- transfer capacity and high infectivity of viral vectors. By learning the molecular mechanisms behind these vectors, nanomedicine and biomedical researchers have developed delivery systems © 2020 American Chemical Society https://dx.doi.org/10.1021/acsnano.0c03697 6383 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective Viral infections are one of the leading causes of morbidity and mortality worldwide and one of the main reasons for significant economic losses.7−9 Standard treatment approaches mainly rely on vaccination and therapeutics derived through targeting key processes in the virus life cycle. However, many viruses evolve subject to selective pressures, often becoming drug resistant, which necessitates additional resources for the development of new drugs. A novel coronavirus causing pneumonia was identified in China in December 2019. On February 11, the Coronavirus Study Group (CGS) of the International Committee on Virus Taxonomy (ICTV) designated the virus as SARS-CoV-2 based on phylogeny and taxonomy.10 The same day, the Director General of the World Health Organization (WHO) designated the disease caused by SARS-CoV-2 “coronavirus disease 2019” (COVID-19). On March 11, 2020, the WHO declared the COVID-19 outbreak a pandemic. As of May 2020, SARS-CoV-2 has spread across the world in over 185 countries, with millions of infections and hundreds of thousands of deaths.11 The main symptoms of COVID-19 are fever (85.6%), cough (68.7%), and fatigue (39.4%). Other less common symptoms include dyspnea, headache, loss of appetite, panting, sore throat, vomiting, diarrhea, rhinorrhea, and abdominal pain. The severity Figure 1. SARS-CoV-2 viral life cycle and potential targets for of disease in patients depends mainly on the presence of nanomaterials. SARS-CoV-2 binds to angiotensin-converting comorbidities such as hypertension, diabetes, and coronary enzyme 2 (ACE2) receptors on the host cell surface. Trans- heart disease.12,13 The incubation period is reported to be membrane serine protease 2 (TMPRSS2) facilitates cellular entry between 5 and 14 days before disease onset.14 Recent reports through protease activity. Later, viral particles are internalized and indicate that some COVID-19 patients exhibit damage in other enter into endosomes. Due to the low pH of endosomes, viral organs such as the heart, kidney, eye (conjunctivitis), and brain particles are uncoated and the viral genome is released for protein (encephalitis).15−18 The race is on to develop drugs and synthesis. Following viral RNA and protein synthesis, new infectious treatment options to combat COVID-19, harnessing all of the particles are assembled and released. tools and technologies modern molecular medicine can offer. The genome of SARS-CoV-2 has been fully sequenced19 and organ failure.25 Notably, a comprehensive protein−protein shows a high degree of similarity in key genes with other interaction (PPI) map of most viral proteins with the human coronaviruses causing respiratory diseases such as SARS-CoV.20 proteome has been established to provide potentially novel Based on knowledge gathered during the SARS-CoV epidemic, a targets for treatment employing already U.S. Food and Drug key target of the virus includes the surface receptor in human Administration (FDA)-approved drugs via a process known as cells, angiotensin-converting enzyme II (ACE2), which is drug repurposing.26 required for efficient uptake in host cells.19,21−23 The development process of antiviral therapies typically The C-terminal domain (i.e., receptor-binding domain of the requires years before the therapies can be made widely envelope-embedded spike (S) 1 protein) of SARS-CoV-2 binds available27 because there are a number of regulatory steps ACE2. The molecular details of this interaction have been required to establish the safety and efficacy of vaccines and provided by solving the crystal structure of the complex.24 drugs.28 Moreover, the highly specific viral targets might change Because binding of the S protein to ACE2 is critical for the first as SARS-CoV-2 continues to mutate, resulting in resistance to steps of infection, the most common treatment approaches focus medication, such as has been observed when attempting to treat on disrupting this key event. At present, there are three main other viral infections. Overviews of the identification of strategies to block ACE2 binding: (i) administration of soluble, candidate drugs for SARS-CoV-2 are detailed in refs 29−31. recombinant ACE2 protein, which acts as a decoy receptor to In the past decade, there has been growing interest in novel, scavenge the virus and, thus, to prevent uptake into host cells;21 broad-spectrum antiviral compounds, which might be less prone (ii) vaccination with antibodies that specifically bind to the S to resistance and could be employed against a wide class of protein and interfere with ACE2 interaction; and (iii) inhibition different viruses, including new variants.32−34 Importantly, such of host proteases that process the S protein and are essential for therapies could be prescribed until more sophisticated, targeted ACE2 binding and subsequent membrane fusion to enable drugs and vaccines are available for each new emerging virus. intracellular delivery of the virus.23 Nanotechnology offers a number of solutions to fight viruses, As shown in Figure 1, the first events of the infection (i.e., the both outside and inside the host, and several nanotechnology- interactions of the virus with the target cells expressing ACE2) based platforms have already been successful in preclinical are in the process of being elucidated at the molecular level. studies to counter several human viral pathogens such as HIV, However, as patients suffering from severe symptomswhich human papilloma virus, herpes simplex, and respiratory usually develop only after several days or a weekalready bear a viruses.32−35 Nanotechnology-based approaches should be high viral load in the lungs, there is a pressing need for strategies leveraged to help the fight against COVID-19 as well as any not only to prevent infection of the host cells but also to attack future pandemics, in a number of ways, including (i) novel pre-existing persistent viruses and to prevent life-threatening vaccines and drugs, where nanomaterials can be leveraged for processes, such as hyperinflammation in the lung and multiple- direct delivery of broad-spectrum antivirals and to support 6384 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective Figure 2. Nanomaterials for prevention and therapy of COVID-19. Integrating nanomaterials into personal protective equipment (PPE) can prevent the entrance of SARS-CoV-2 in the respiratory system. Nanomaterials could also be used to deliver drugs to the pulmonary system via inhalators. Cellular binding of viral particles at the alveoli can be inhibited using targeted nanoparticles (NPs) against angiotensin-converting enzyme 2 (ACE2) receptors or viral S protein. Various mechanisms can be used to inactivate viral particles systemically such as using neutralizing NPs or photocatalytic nanomaterials. Nanomaterial-based vaccines or immunomodulation can be used to prevent SARS-CoV-2 infection or even to boost the immune response during infection. PDT, photodynamic therapy. targeted therapies to the lungs; (ii) highly specific, rapid, and actively pursuing ideas to deliver drugs, therapeutic proteins, sensitive tests to detect infection or to detect immunity and mRNAs by exploiting nanodevices for pulmonary (serological tests); (iii) superfine filters for face masks or delivery.38,39 blood filtering; (iv) novel surfaces or surface coatings that are Moreover, the rapid emergence of SARS-CoV-2 has exposed resistant to viral adhesion and can inactivate the virus; and (v) one of the main weaknesses in the current medical landscape: the improvement of tools for contact tracing (Figure 2). the lack of broad-spectrum antiviral drugs. At present, there are This crisis has also highlighted the importance of rapid only a handful of approved antivirals, and they are mostly virus- prototyping/manufacturing for addressing unforeseen needs, specific. Hence, when a new virus emerges, little can be done such as in case of a pandemic, where large-scale production of pharmacologically to slow down its spread. Some research equipment including ventilators and personal protective equip- efforts have been focused on the development of broad- ment (PPE) is urgently needed and nanotechnology may aid spectrum drugs, which could potentially offer some efficacy (e.g., in providing readily synthesizable materials for equipment against future emerging viruses (and maybe SARS-CoV-2). The manufacturing as well as for the improvement of their efficiency various approaches developed over the years are mainly based and durability). In the next sections, we expand and elaborate on on the creation of entry inhibitors.40,41 A highly conserved part the specific contributions that nanotechnology can offer to in viruses is the attachment ligand (VAL). In most known counter COVID-19 and similar pandemics. respiratory viruses,42 the VAL targets either heparan sulfate proteoglycans (HSPG)43 or sialic acids (SA).44 Both HSPG and NANOTECHNOLOGY TOOLS TO INACTIVATE SA mimics have shown in vitro ability to bind to viruses, blocking SARS-CoV-2 IN PATIENTS their interaction with cell membranes, and often in a broad- The main target of SARS-CoV-2 is the respiratory tract (upper spectrum way.45−47 airways, lung),36 although other organs might also be infected In the context of nanomedicine, many nanomaterials have (e.g., gut, kidney) and vasculature21 also appears to be a prime been developed, ranging from polymers48 to dendrimers,49 target. The expression of ACE2 probably determines uptake by oligomers, NPs,50 liposomes,51 and small molecules.52 However, different tissues.37 successful clinical translation has been hindered by the fact that, In addition to discussing immune-based approaches, because upon dilution, these compounds lose efficacy as the virus- the lung is the most critically affected organ, we will center our compound complex dissociates leaving viruses free to restart discussion on the various options to inactivate the virus in the their replication cycle. Recently, it has been shown that this deep lung and to target the essential host cells for drug delivery. limitation can be overcome by synthesizing NPs that, after The virus reaches the alveoli and enters alveolar epithelial type II binding, are able to inhibit viral infectivity irreversibly by cells (AECII), due to the relatively high abundance of ACE2 and permanently damaging the virion, refueling the hope for a true, a permissive cellular milieu. These cells serve as a reservoir of the broad-spectrum antiviral drug.53 Because the focus is also on the virus, which finally spreads throughout the lung, leading to the development of a drug specific to SARS-CoV-2, a good entry lung function impairment seen in severe cases. Airborne inhibitor could be based on blocking the S spike protein nanomaterials are optimally suited to penetrate into the deep interaction with the cellular ACE2 receptor.19,21−23 Regardless lung due to the physicochemical properties of such aerosols, of the specific approach, it is imperative that novel, effective existing on the same size scale particles that penetrate most antivirals be based on compounds that exhibit very low or readily to the deep airways. Hence, nanomedicine is already negligible toxicity profiles, as patients will most likely need to 6385 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective receive those drugs for extended periods of time and will already improving protein delivery and pharmacokinetics over conven- be weakened. For these reasons, when designing antiviral drugs, tional approaches.38 Intranasal delivery of polymer-encapsulated clearance mechanisms have to be kept in mind. An example of antigen triggers a strong immune response, and the success of this process is the recent redesign of broad-spectrum antiviral vaccination depends on the appropriate type of polymer in NPs into equally effective modified cyclodextrins.54 Moreover, combination with the antigen.61,62 Similarly, researchers have nanotechnology may offer nanotheranostic approaches to fill the developed lipid and lipid-based NPs as delivery platforms for existing gap between diagnostics and therapy.55−57 The mRNAs or siRNAs to enable the synthesis of key viral proteins simultaneous management of both diagnostics and therapy for for vaccination or to inactivate critical viral target genes, those suffering from COVID-19 or in future pandemics, as for respectively.39 The field of therapeutic mRNAs to support many other diseases, is an additional potential strategy to take vaccination has gained momentum, as well,63 at least in part due into consideration in which nanomaterials have proven to be to nanotechnology-enabled strategies for cargo delivery. More- effective tools. The advantages of the capabilities of nano- over, the versatility of nanoplatforms as antigen-presenting technology and nanomaterials for combined therapeutics and systems offers great opportunities. Considering the possibility of diagnostics has been widely explored in cancer research; random viral mutations that may alter the antigen shape, however, there have been considerable efforts in the past few functionalizing nanomaterials with a wide number of molecules years to extend the scope of this approach to other areas at the same time to target the virus, or motifs that are specific for including infectious diseases.58 pathogens, will increase the efficiency of vaccines and their Nanomaterial-Based Vaccine Development and Im- ability to prevent viral infection. munomodulation. Following the publication of the genetic Several companies are working on mRNA vaccines encoding sequence of SARS-CoV-2 on January 11, 2020, intense research SARS-CoV-2 proteins such as the spike protein, encapsulated in efforts have been devoted to developing a vaccine against nanoliposomes with specific physicochemical properties that are COVID-19. With unprecedented speed, this extraordinary potentially akin to those documented for immunization against scientific mobilization led the first vaccine candidate to enter certain tumor antigens.64 The design of such nanocarriers, which the Phase I human clinical trial on March 16, 2020, and other will need to escape recognition by scavenger cells and to be novel candidates are rapidly following.59 Up to May 22, 2020, nontoxic and nonimmunogenic, is a challenge that will require there are 10 COVID-19 candidate vaccines in clinical substantial time prior to clinical availability. evaluations and 114 in preclinical development.60 On March 16, 2020, Moderna, through a partnership with the Concerning vaccine and immunization research, nanomateri- Vaccine Research Center at the U.S. National Institutes of als can assist in multiple ways to boost the upregulation required Health, enrolled the first participants into a Phase I clinical trial by the immune system and to direct the immune response testing an mRNA vaccine (mRNA-1273) encapsulated in lipid specifically against antigens. Immune-targeted nanotherapeutics NPsa record time of just 63 days following sequence selection can be developed through their rational manufacture at the (NCT04283461).65 The enrollment of the first cohort of nanoscale level by designing nanomaterials that are able to participants (18 to 55-year-old healthy subjects) concluded on amplify host’s immune response, for instance as adjuvants in the April 16, 2020.66 CureVac and BioNTech (in partnership with context of vaccination. Pfizer) are currently working on similar vaccines; Pfizer/ BioNTech, in particular, have recently started the recruitment Immune-targeted nanotherapeutics in Phase I/II trials (NCT04368728, NCT04380701). A DNA can be developed through their ra- plasmid vaccine by Inovio Pharmaceuticals (INO-4800) has showed promising results in mice and guinea pigs according to a tional manufacture at the nanoscale recent article published in Nature Communications67 and has level by designing nanomaterials that entered Phase I testing in humans (NCT04336410). are able to amplify host’s immune Another candidate COVID-19 vaccine for Phase I clinical trial response, for instance as adjuvants in is from the University of Oxford and AstraZeneca (NCT04324606).68 Around 1110 people will take part in the the context of vaccination. trial, which started recruitment at the end of April 2020. The vaccine is based on a chimpanzee adenovirus vaccine vector The development of a vaccine will rely either on the direct (ChAdOx1) and the SARS-CoV-2 spike protein. Chimpanzee administration of viral antigens (e.g., in the form of recombinant adenoviral vectors against different pathogens have been already proteins, vectored vaccines, or whole inactivated or attenuated tested in thousands of subjects with demonstrated safety. To virus) or RNA- or DNA-encoding viral antigens.27 Candidate date, ChAdOx1 has been administered to six rhesus macaques antigens for immunization are surface proteins such as the exposed to high doses of SARS-CoV-2. The vaccine was unable immunogenic spike protein (S1), which is already targeted by to prevent infections, although it reduced the severity of the antibodies of convalescent patients.27 Because the S1 protein is disease: no signs of virus replication were observed in the lungs, also essential for cellular uptake, many researchers are using this with significantly lower levels of respiratory disease and no lung protein as the primary target for a vaccine. damage compared to control animals, according to a recent There are many issues related to the delivery of a drug, article deposited in bioRxiv.69 Another adenoviral vector vaccine protein, or RNA into the patient as the cargo is often degraded, developed by CanSino Biological Inc. and Beijing Institute of not bioavailable, or is swiftly cleared. Nanotechnology provides Biotechnology using a genetically engineered replication- multiple solutions to these challenges though, as nanocarriers defective adenovirus type 5 vector to express the SARS-CoV-2 can overcome some of these limitations. spike protein (Ad5-nCoV) is currently being tested in Phase I/II Biocompatible polymeric-, lipid-based, or inorganic NPs can trials (NCT04398147, NCT04341389, NCT0431312). be tuned with respect to their physicochemical properties to Although vaccines based on novel DNA and mRNA encapsulate cargo proteins with high loading efficiency, technologies might be promising, there are no such kinds of 6386 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective vaccines on the market, and it is unknown whether they can be which activates the ACT-NLRP3 inflammasome pathway;79 and effective in humans. Moderna, for instance, has generated (d) AS04 (used for hepatitis B and human papilloma virus preliminary safety data on different mRNA-based vaccines vaccines), which is a combination of MPL and aluminum targeting other respiratory viruses, but their more advanced hydroxide.76,80 program (on a cytomegalovirus vaccine) is still in Phase II In this context, the concept of “nanoimmunity by design” clinical testing. However, on May 18, Moderna announced that relies on the rational design of distinct physicochemical mRNA-1273 elicited antibody titers above the levels observed in properties and specific functionalization of nanomaterials convalescent individuals (and therefore considered potentially intended for fine-tuning their potential effects on the immune protective) in all eight initial participants across the 25 and 100 system.81 Nanomaterials have emerged as promising tools for μg dose cohorts of the Phase I trial (NCT04283461).70 The immune modulation, either stimulating or suppressing the company, after having received a fast-track approval from the immune response. In fighting SARS-CoV-2, these properties FDA, is now moving on Phase II trials. may find applications for both prevention and therapy and in the Conversely, strong evidence exists regarding the efficacy of context of vaccine development. protein-based vaccines such as recombinant-protein, viral- vector, attenuated, or inactivated vaccines across different Nanomaterials have emerged as infectious diseases, with licensed vaccines already existing for all of these platforms.27 All of the aforementioned approaches promising tools for immune modula- are currently being explored in the context of SARS-CoV-2.27 An tion, either stimulating or suppressing inactivated vaccine developed by the China National the immune response. Pharmaceutical Group (Sinopharm), in collaboration with the Wuhan Institute of Biological Products, is currently tested in a Mounting evidence indicates that nanomaterials such as Phase I/II trial (ChiCTR2000031809), and a second inactivated graphene,82 nanodiamonds,83 carbon nanotubes,84 and poly- vaccine (in collaboration with the Beijing Institute of Biological styrene particles85 bear an intrinsic capacity to activate the Products) has been currently approved for clinical testing immune system, depending on their functionalization.86 For (ChiCTR2000032459). A third aluminum salt (alum) adju- instance, graphene oxide functionalized with amino groups vanted inactivated vaccine, developed by Beijing-based Sinovac (GO-NH2) induces activation of STAT1/IRF1 interferon Biotech’s, was able to provide partial or complete protection in signaling in monocytes and T cells, resulting in the production rhesus macaques, according to a recent article published in of T cell chemoattractants, and macrophage 1 (M1) 1/T-helper Science,71 and is currently being tested in Phase I/II trials 1 (Th1) polarization of the immune response, with negligible (NCT04383574, NCT04352608). toxicity.82 Remarkably, the ability of licensed adjuvants such as Live-attenuated vaccines are intrinsically immunogenic (e.g., AS01 and AS03 to enhance adaptive immunity has been linked due to the presence of viral DNA), but extensive safety tests are to their capacity to boost STAT1/IRF1 interferon signaling.87 In required due to the rare possibility of reversion to a pathogenic addition, recent SARS-CoV and MERS-CoV studies suggest form able to cause infection. Vaccine candidates based in this that the development of a Th1-type response is central for application have previously been designed for SARS-CoV with controlling infection, which also may be true for SARS-CoV-2.88 high stability.72,73 Recombinant-protein vaccines and inacti- Several groups and consortia have been screening and vated vaccines are safer but might require adjuvants to increase characterizing nanomaterials according to their immunomodu- their immunogenicity. In the context of SARS-CoV-2, adjuvants latory properties and absence of cytotoxicity.56,57,82−84,86 The are important for two reasons. First, adjuvants might increase the development of an adjuvant for clinical use is a lengthy process efficacy of the vaccine, especially in subjects with impaired that requires extensive Phase III randomized trials in large and immunological function, such as the elderly, or in subjects with diverse cohorts of subjects, and the process generally requires comorbidities resulting in immune dysfunctions; in these patient several years.76 Pharmaceutical giants such as GlaxoSmithKline cohorts, SARS-CoV-2 has a high lethality rate. Second, (GSK), which owns the ASs mentioned above and other adjuvants can reduce the amount of vaccine protein(s) required adjuvant platforms, are engaged in several partnerships to embed per dose, which could facilitate scaling-up vaccine production in their adjuvant systems with SARS-CoV-2-protein-based vac- a reduced time frame. cines. A full-length recombinant SARS-CoV-2 glycoprotein Beyond alum, which is in fact a nanoscale material74 that was nanoparticle vaccine adjuvanted with the saponin-based Matrix developed in the 1920s for the tetanus and diphtheria toxoids,75 M developed by Novavax is in Phase I clinical testing approval for a new adjuvant did not occur until 1997, with the (NCT04368988).89 introduction of the oil-in-water emulsion of squalene oil and Although it is unlikely that novel adjuvants would be used in polysorbate 80 and sorbitan trioleate surfactants (MF59) in the the context of the current pandemic, the SARS-CoV-2 pandemic seasonal influenza vaccine for the elderly.76 The use of MF59 offers an opportunity to reflect on the potential of nano- was further expanded to pandemic and avian influenza technology for vaccine adjuvant development. In this context, it vaccines.77 Other adjuvants in licensed vaccines have been is critical to stream coherent pipelines covering in vitro and in approved since 2000, as well: (a) AS03 (used for pandemic and vivo experiments specifically to select candidate materials that avian influenza vaccines), similar to MF59, but including α- might be tested for clinical implementation as vaccine tocopherol as an additional immune stimulant; (b) AF 03 (used adjuvants.90 for pandemic influenza vaccines), an alternative squalene In this view, the status of nanomaterial-based vaccine emulsion containing polyoxyethylene, cetostearyl ether, man- adjuvants has been reviewed.91,92 In particular, immunomodu- nitol, and orbitan oleate;78 (c) AS 01 (used for herpes zoster latory effects induced on the innate immune signaling have been vaccine), a liposome-based vaccine adjuvant system containing demonstrated.91 For example, nanomaterials such as GO can two immunostimulants, 3-O-desacyl-4′-monophosphoryl lipid elicit an inflammasome sensor (NLRP3)-dependent expression A (MPL, a Toll-like receptor 4 agonist) and saponin QS-21, of IL-1β in macrophages.93 Notably, alum, the most commonly 6387 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective used adjuvant in human vaccines, induces the release of this difficulties in gas exchange. Through nanomedicine, we envision cytokine in macrophages through the same NRLP-induced therapeutic approaches aimed at targeting specific immune mechanism. These results suggest that nanomaterials such as subpopulations to avoid these complications, and different GO and alum may be useful for medical applications.94 nanomaterials have already been explored for their specific Considering that new vaccine development typically requires impact on different immune cell subpopulations.82,83,86 years to be approved and applied to the general population, Octadecylamine-functionalized and dexamethasone-adsorbed there is also an urgent need to study how to improve treatment nanodiamond promotes anti-inflammatory and proregenerative approaches. According to the first Phase III clinical studies, the behavior in human macrophages in vitro.101 A low dose of this antiviral drug Remdesivir, which was recently approved by the functionalized nanodiamond also reduced macrophage infiltra- FDA for COVID-19 treatment in the United States, seems to be tion and expression of proinflammatory mediators iNOS and a promising treatment for adults diagnosed with COVID-19. tumor necrosis factor (TNF)-α in mice. Overall, these results Nano-based strategies have already been applied to enhance the suggest that nanodiamond particles may be useful as an effectiveness of Remdesivir in the context of other emerging viral inherently immunomodulatory platform. infections (Nipah virus),95 suggesting the suitability of nano- technology to assist with similar strategies for the treatment of Nanosystems can enhance the specif- COVID-19 as well as other possible pandemics in the future.96 Can Nanotechnology Help to Control the Cytokine icity/efficiency of immunosuppressant Storm? One of the main features of COVID-19 is the triggering delivery to target immune cells, with of a cytokine storm in the body, also known as cytokine release consequent reductions in drug dose, syndrome (CRS), which results from an excessive immune drug distribution to nontarget tissues response and leads to the severe deterioration of patient health.25,97,98 This inflammatory storm is one of the major and organs, and possible side effects. causes of the acute respiratory distress syndrome (ARDS) that is often associated with multiple-organ failure, representing the Finally, the indiscriminate systemic suppression of the leading causes of death in critical patients.98 In particular, the immune system may increase the susceptibility to sepsis due role of interleukin (IL)-6 has been highlighted in patients to underlying secondary bacterial infections that can exacerbate requiring assisted ventilation. Ongoing clinical trials are testing critical conditions in patients, causing death.102 Risk factors for drugs that block the receptor of IL-6 (Tocilizumab, an anti-IL-6 mortality include acquired bacterial infections by opportunistic receptor antibody, and Sarilumab) or IL-6 itself (Siltuximab). organisms and primary pathogens. Using nanocarriers to achieve Whereas a well-regulated cytokine response that is rapidly targeted delivery of immunosuppressive drugs, or the specific triggered by the host’s innate immunity can serve to prevent and and controlled inhibition of only a specific immune cell to counteract an infection, an excessive, unbalanced, prolonged subpopulation, can play a critical role in limiting such immune response can seriously harm the body. Therefore, complications. therapeutic strategies aimed at effectively suppressing the The fast and complete removal of pro-inflammatory cytokines cytokine storm are under investigation. Nanomaterials have from the bloodstream has been shown to increase survival been exploited to adjust the immune response to an optimized significantly in patients with early stage sepsis. Adsorption of level, and such proprieties might be explored to inhibit cytokine cytokines from serum by extracorporeal perfusion through releases.99 Nanosystems can enhance the specificity/efficiency porous carbons is one of the most promising ways for their of immunosuppressant delivery to target immune cells, with selective, quick, and complete removal from blood circulation. consequent reductions in drug dose, drug distribution to Hierarchical carbon materials with tuned porosity have shown nontarget tissues and organs, and possible side effects. In effective adsorption of many cytokines, including IL-6 and even addition, specific nanotools can be designed to evade the the largest ones, such as TNF-α.103 Based on their demonstrated immune system and to enhance the solubility of poorly soluble outstanding performance in removing sepsis-associated pro- immunosuppressant agents; the potential of finely tuning their inflammatory cytokines from blood, mesoporous carbon surface charge opens possibilities for encapsulation strategies adsorbents with hierarchical structure, tuned pore size, and and offers accommodation for a high drug load. All of these surface chemistry, as well as graphene with open and accessible mechanisms may also occur simultaneously, enhancing the surfaces104 have significant potential to quickly remove activity of immunosuppressive agents. inflammatory cytokines associated with CRS and to prevent Concerning the role of macrophages in COVID-19, the mortality arising from an uncontrolled inflammatory cascade, presence of ACE2-expressing CD68+CD169+ macrophages thereby providing enough time for the defense mechanisms of containing SARS-CoV-2 nucleoprotein antigen and showing an the human body to fight the virus. increased release of IL-6 was observed in infected spleen and Photodynamic Inactivation of SARS-CoV-2. In addition lymph nodes.100 Notably, immunohistochemical and immuno- to drug- and vaccine-based antiviral strategies, photodynamic fluorescence analyses of lymph nodes and spleen tissue from therapy (PDT) stands as a unique approach to inactivate SARS- autopsy samples of patients who died from COVID-19 revealed CoV-2. Using a light-based method, PDT attacks target cells via lymphocytic apoptosis. The tissues infected by SARS-CoV-2 the excitation of photosensitive agents, called photosensitizers also showed an upregulated expression of Fas, suggesting a role (PSs), with radiation characterized by a wavelength correspond- for CD169+ macrophages in viral spreading, aberrant inflam- ing to its absorption spectrum to generate reactive oxygen mation, and activation-induced lymphocyte apoptosis. More- species (ROS) in the presence of oxygen, which ultimately over, histological examinations of biopsy samples of patients results in cell death. Photodynamic therapy is primarily used for who died from COVID-19 revealed an increased alveolar the clinical treatment of various oncological disorders.105 It was exudate due to the extended neutrophil and monocyte infiltrate not until the 1970s that PDT was first used clinically against in lung capillaries with fibrin deposition, probably leading to viruses,106 exploiting ROS production to damage virus proteins, 6388 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective nucleic acids, andif presentlipids.107 Even though there are size, charge, shape, and surface features that can be chemically research efforts for PDT-based virotherapies against different functionalized to resemble proteins. These similarities can be viruses, including herpes simplex virus, human papilloma virus, used in biotechnology to control virus pathways or cell receptor and human immunodeficiency virus,106−109 clinical use of PDT interactions with NPs.120 is limited due to hydrophobicity of PSs, poor target specificity, Among the many attempts, the legendary accomplishments, and limited tissue penetration ability. and the epic failures, we could list thousands of different NPs, Most PSs are hydrophobic and aggregate in aqueous differing from one another thanks to the creative endeavors of solutions, affecting their photochemical and photobiological their designers. Despite their remarkable differences and properties.106,110 For this reason, Lim et al. have proposed a researchers’ endeavors to make them one of a kind, they all promising approach for photodynamic inactivation of viruses aim to achieve one goal: to deliver in a specific way one particular with NPs, developing sodium yttrium fluoride (NaYF4) form of payload, while remaining as unnoticed as possible by the upconversion NPs (UCNs) with zinc phthalocyanine PSs body’s defense mechanisms. For everyone who has made an grafted onto their surfaces. Unlike most PSs, these UCNs are effort to create their own version of such a silver bullet, it has coated with polyethylenimine (PEI), which render them come to mind that nature in its incredible variety had already hydrophilic and easier to manipulate. These UCNs showed invented a few ingenious solutions to this problem. In the world antiviral activity against Dengue virus serotype 2 and adenovirus of nano-based drug delivery, one entity dominates as the type 5, which were used as models of enveloped and non- quintessential example of precision, efficiency, and stealth: the enveloped viruses, respectively.110 MXenes111,112 are a large virus. Not by chance, these two worlds share many features that family of 2D transition metal carbides, nitrides,113 and span from the physical laws that govern their assembly and carbonitrides114 that exhibit unique electronic, optical, and stability to the chemical similarities in their overall composi- catalytic properties. They have the general formula Mn+1XnTx, tion.121 where M is an early transition metal (Ti, Zr, V, Mo, etc.), X is C Historically, the field of nanomedicine and the global and/or N, Tx represents the surface functional groups (O, endeavor to generate NPs for drug delivery arose from one of −OH, −F, −Cl), and n = 1−4.115,116 Some examples include the greatest struggles in medicine: gene therapy. At the core of Ti3C2Tx, V2CTx, and Nb2CTx, with over 30 stoichiometric that approach was the idea that viruses could be used as Trojan compositions already synthesized with more than 100 predicted. horses to deliver the correct sequence of the gene into the cells Biocompatible MXenes, such as Ti3C2Tx, are hydrophilic and that harbored the mutated copy. In order to identify the virus are among the most efficient light-to-heat transforming that offered the best delivery service, a cadre of viral strains and materials.117 The plasmon resonance extinction maxima of species were tested, adapted, and engineered to fit the aims and Ti3C2Tx is at 780 nm, enabling the use of near-infrared (IR) light hit the targets. It took decades of trial and error, of progressive for PDT. Several other MXenes have absorption maxima in the adjustments, and a few tragic mistakes to identify the viruses that IR range and have shown outstanding performance in PDT and could provide the ideal backbone to develop viral vectors able to theranostic applications.118 ferry genetic cargo into the target cell.122 In the midst of that Fullerene and graphene are also good candidates for virus global challenge, nanotechnology offered a safer and more inactivation by PDT and have proved to be effective against controllable alternative: to generate bespoke structures that Semliki Forest virus (SFV), vesicular stomatitis virus (VSV), could replace viral vectors and do the same job, delivering a HSV-1, HIV-1, mosquito iridovirus (MIV), and influenza A payload from the point of injection to the site of action. virus (IAV), as well as the phage MS2.107 In addition, several 2D Fast forward a few decades, and the promises made by both nanomaterials, including graphene-based materials, MXenes, worlds seem to have finally become reality, with a number of black phosphorus, graphitic carbon nitride, tungsten disulfide, active clinical trials, some clinical success stories, and a few and molybdenum disulfide, have been reported to improve the commercial products in the market space. Interestingly, the two efficacy of PDT considerably for cancer treatment.56,57 There- worlds seem to have maintained a safe distance so as to avoid any fore, determining if such nanomaterial-based PDT protocols collision or dangerous proximity. Exchange of ideas between the could be exploited to inactivate SARS-CoV-2 is of great interest. fields of gene therapy and nanomedicine is limited, and the Biomimetic Engineering of Nanodelivery Systems: potential for disciplinary growth through knowledge exchange Artificial Viruses in the Making. In an effort to engineer the has remained elusive to scientists in both fields.5 Many scientists next generation of nanoscale vectors, scientists have moved from have suggested that nanotechnologists could find inspiration in using inorganic components aimed at obtaining inert structures the mechanisms devised by viruses to elude immune to utilizing biological building blocks that are able to convey surveillance, to overcome biological barriers, and to deliver additional functionalities to the resulting construct. To cope their genetic payload with high specificity. Similarly, gene with the complexity of the body and to evade the multiple layers therapists would find high-tech solutions to their scalability and of defense that tissues and organs have, it is critical to rely on the safety issues in looking at the new generations of biomimetic ability of certain materials to interact with, rather than to eschew, particles being generated. the biology of our body. Every NP system conceived to date The principles of biomimicry and bioinspiration have been faces one common fate: whether injected, inhaled, ingested, or used to design and to engineer drug-delivery technologies that absorbed through our epithelia, all will at some point come into reproduce or recapitulate biological materials, for what pertains contact with the mixture of fluids and organic compounds that to not only their structure and chemistry but also, more comprise the body. Under such conditions, every material reacts importantly, their functions. In drug delivery, surface recog- in a unique way according to the conditions they individually nition and nanoscale interactions between materials and face (i.e., the tissue or body region they are in), their biological entities are key to the success of the delivery strategy, composition (i.e., organic or inorganic), and their physical and the use of biological building blocks such as membrane properties (i.e., size, shape, surface charge).119 Inorganic NPs proteins has been proposed as a way to convey targeting and can function as globular protein mimics because of their similar shielding moieties simultaneously.123 One can only hope that 6389 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective the recent events and global attention that viruses are capturing investigational drugs outside the scope of the original medical in the scientific world will spur a renewed interest in finding ways indication that can be used to fight COVID-19.130,131 There are to adapt viral features and mechanisms of action to the world of various advantages to this strategy, including already-established NPs. Increased focus in this field would be useful to create virus- safety profiles, fast transition to clinical studies, and less like NPs able to circulate in the blood system, overcoming the investment needed, compared to the process of developing an endothelial barrier, and to deliver their therapeutic payload with entirely new drug.132,133 Therefore, these advantages have the high efficiency.124 potential to result in less risky and more rapid returns on Interference with Cellular Uptake, Immobilization, investment in the development of repurposed drugs, benefits and Inactivation of the Virus Outside of the Host Cell. that are particularly important during pandemics. In addition to Nanomaterials can be synthesized with a high specific surface rapid diagnosis, making recommendations to physicians about area of a few hundred square meters per gram. Therefore, rapid treatment methods can save the lives of many people. dependent on the surface properties, nanomaterials efficiently Combining in silico tools such as molecular docking, molecular adsorb biomolecules and form a so-called biomolecular corona. dynamics, and computational chemistry with large drug This passive, nontargeted adsorption might be utilized to bind databases provides a great advantage in selecting “possible viruses, provided that the selected nanomaterial is relatively candidates” from among thousands of pharmaceutically active biocompatible. Viral surface proteins are often modified by sugar substances (Figure 3). In silico analyses should be supported by moieties or encompass positively charged amino acid patches that bind to lectins or glycosaminoglycans (GAGs) of heparan sulfate (HS), respectively.32 Robust interactions of virus particles with these host receptors is ensured by multivalent binding, which is likely why single-molecule inhibitors often are not capable of efficiently perturbing this key event but multivalent NPs are superior to block binding of different viruses to the host cell.125 Gold NPs capped with mercaptoethanesulfonate are effective inhibitors of HSV type 1 infection as they mimic cell-surface- receptor heparan sulfate and, therefore, competitively bind to the virus. Interestingly, polyvalent sulfated Au NPs inhibit virus binding to the host cell dependent on their size. Nanoparticles of diameters equal to and larger than the virus diameter (in this case, the stomatitis virus) more efficiently inhibit the binding to cells than smaller particles. Most likely, larger NPs efficiently Figure 3. Schematic of how in silico analysis can be used to select cross-link virions, whereas smaller NPs simply decorate the viral candidate drug molecules for clinical studies. MD, molecular surface.126 Papp et al. found that gold NPs decorated with SA dynamics. effectively inhibited the binding of influenza virus to the target cells. In this case, viral recognition via its surface protein the literature, expert opinions (pharmacologists and clinicians), hemagglutinin of SA on the host cell membrane was a and, when possible, preclinical and clinical findings. After prerequisite for cellular entry.127 More recently, Cagno et al. selecting the best candidates following in silico analyses, detailed reported antiviral NPs (Au and iron oxide core) with long and in vitro and in vivo experimentation should be undertaken prior flexible linkers mimicking HS that strongly bind and inactivate to clinical studies. Recently, various drug-repurposing studies viruses such as respiratory syncytial virus in vitro and in vivo in a have been published to assist in the global COVID-19 pandemic lung infection model and even led to irreversible viral response.134−136 Such studies aim to identify whether already- deformation.53 Hence, there is ample evidence that biocompat- approved drugs have the capacity to interact with viral proteins ible, functionalized NPs can act as broad-spectrum antivirals. or receptors on host cells. Notably, the receptor-binding domain of the spike S1 protein of In nanomedicine, computational models have recently SARS-CoV-2 binds not only to ACE2 but also to heparin128 and, garnered attention; such work may help to identify how thus, might be targeted by similar approaches as outlined above. nanomaterials interact with biological systems and to determine how the efficacy of these nanotherapeutics could be improved. There is ample evidence that biocom- Computational models indicate how NPs are taken up by patible, functionalized nanoparticles healthy cells or tumor cells, enabling better predictions regarding the pharmacokinetic and pharmacodynamic proper- can act as broad-spectrum antivirals. ties of these materials.134 For example, Lunnoo et al. used a coarse-grained molecular dynamics (MD) simulation to observe One of the most recent strategies to inhibit viral uptake is the internalization pathways of various Au nanostructures based on administration of recombinant ACE2 to inhibit (nanospheres, nanocages, nanorods, nanoplates, and nano- binding competitively via the spike S1 protein.21 Knowing that hexapods) into an idealized mammalian plasma membrane.137 multivalency is key to block virus−host interactions reliably, Other studies have simulated how different NPs can target researchers have speculated that a nanostructured carrier could tumor cells and deliver drugs.138,139 Therefore, in silico not only improve delivery and cargo stability but also might approaches that are currently used for drug repurposing, dramatically enhance binding strength.129 including molecular docking, molecular dynamics, and Speeding up the Nanomedicine-Based Approaches computational chemistry, constitute valuable tools to aid for COVID-19 by In Silico Analysis. Currently, repurposing preclinical and clinical studies of nanomaterials directed for drug molecules is a key strategy for identifying approved or disease treatment. Considering the urgent need for nano- 6390 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective medicine against the current pandemic, in silico analyses may be being able to detect 1000 fg μL−1 of nucleic acid quantitatively especially useful in guiding the rational design of new NP (Figure 4).145 formulations required to fight SARS-CoV-2. Paper/nanomaterial-based sensors,146,147 in general, and, particularly, NP-based lateral-flow devices that are observed NANOTECHNOLOGY TOOLS TO DETECT SARS-CoV-2 with the naked eye or operated through a smartphone are now Standard procedures for detecting the virus from nasophar- the most reported testing platforms for the analysis of COVID- yngeal and/or oropharyngeal swabs have been reviewed recently 19-related biomarkers.148 Nanopaper147 and nanochannels149 and are primarily based on reverse transcription polymerase may also offer cost-efficient alternatives for detection of viruses chain reaction (RT-PCR).140 Here, we would like to mention and related biomarkers. Nanomaterials are already being used in some preliminary ideas on nanotechnology-based assays to theranostics applications. Although the field of nanomaterial monitor the presence of SARS-CoV-2. A simplified test and applications in nanotheranostics is still in its infancy,55 a variants thereof to detect viral proteins (e.g., HIV or influenza thoughtful review of the performance characteristics of known virus) without the need for expensive equipment is based on the nanomaterials may open new avenues of investigation, even for color change of Au NPs bound to antibodies. Similar to the COVID-19-related applications (for both diagnostic and enzyme-linked immunosorbent assay (ELISA) antibodies therapies, including vaccines). coupled to Au NPs will form a tertiary complex with the viral antigen and a capture antibody, thereby leading to the NANOTECHNOLOGY TOOLS TO INACTIVATE immobilization and agglomeration of NPs, which shifts the SARS-CoV-2 IN DIFFERENT ENVIRONMENTS OUTSIDE color from red to blue.32 Such simple, low-cost procedures could THE PATIENT be of value in regions with low-resource medical infrastructure, SARS-CoV is highly stable at room temperature and at 4 °C, but as found in developing countries. For rapid, on-site detection, it is inactivated by ultraviolet light at 254 nm, highly alkaline or the development of graphene-based field-effect transistor (FET) acidic conditions of pH >12 or pH <3, respectively, or by brief biosensing devices coupled to a specific antibody against SARS- (e.g., 5 min) heat treatment at 65 °C. SARS-CoV-2 is expected CoV-2 spike protein was recently reported.141 Dual-functional to be similarly sensitive.150 Several human coronaviruses can be plasmonic biosensors combining the plasmonic photothermal inactivated by classical disinfectants, including bleach, ethanol, (PPT) effect and localized surface plasmon resonance were also povidone-iodine, chloroxylenol, chlorheximide, and benzalko- recently developed and could be used as a cost-effective and fast nium chloride,151 so we expect similar inactivation with SARS- alternative to RT-PCR. Here, Au nanomaterials coupled to CoV-2. The virus stability on surfaces depends on the complementary DNA sequences are used to sense hybridized composition of the infected material, with inactivation in <3 h cDNAs of SARS-CoV-2.142 on printing and tissue paper, in <2 days on treated wood and Nanobiosensors are a valuable alternative to conventional cloth, in <4 days on glass and banknotes, and in <7 days on laboratory equipments for clinical and environmental anal- stainless steel and plastic.152 Conversely, active viruses can yses.143 Usually, nanobiosensors combine the excellent electrical remain on the outer layer of a surgical mask even after 7 days.152 and optical properties of nanomaterials with biological or The surface and aerosol stability of SARS-CoV-2 is comparable synthetic molecules used as receptors to detect selectively any to that of SARS-CoV-1,153 with both viruses remaining viable in kind of analyte. The detection of whole cells (e.g., cancer cells) contaminated aerosols for more than 3 h. Infectious SARS-CoV- using electrocatalytic properties of Au NPs toward hydrogen 1 and SARS-CoV-2 remain viable up to 72 h after inoculation on evolution has been reported.144 This cell-sensing device is based plastic and stainless steel, whereas both are inactivated on on the reaction of cell surface proteins with specific antibodies copper in less than 4 or 8 h, respectively, and on cardboards in conjugated to Au NPs. The same detection technique can also less than 24 and 8 h, respectively.153 Therefore, the stability of be applied to the detection of viruses, taking advantages of the both viruses is similar, and we can hypothesize that surface known antigens and available antibodies. Recently, as treatments with NPs that proved to be effective for SARS-CoV-1 mentioned above, a FET sensor (modified with graphene could possibly also be effective for SARS-CoV-2. sheets) that uses a specific antibody against SARS-CoV-2 spike Nanotechnology can offer alternative methods to classical protein was reported to detect SARS-CoV-2 in culture medium disinfection protocols used in healthcare settings, which (limit of detection, LOD: 1.6 × 101 pfu/mL) and clinical typically rely on chemical-based disinfection using hydrogen samples (LOD: 2.42 × 102 copies/mL).141 peroxide stream or metal-ion-coated surfaces, biological-based strategies including probiotics or biosurfactants, or physical Nanobiosensors are a valuable alter- strategies such as irradiation with ultraviolet (UV) light. native to conventional laboratory Nanotechnology may offer pathways to the development of self-disinfecting surfaces that would avoid contamination of the equipments for clinical and environ- healthcare and housekeeping staff. mental analyses. Nanotechnology may offer pathways to the development of self-disinfecting Researchers have also demonstrated solid-phase isothermal surfaces that would avoid contamina- recombinase polymerase amplification (RPA) for the detection tion of the healthcare and housekeep- of Citrus tristeza virus (CTV) for plant disease diagnostics. Gold ing staff. NPs linked with DNA strands on top of an electrode were used to detect in situ amplified CTV (RPA assay for amplification of the P20 gene, 387 bp) using electrochemical impedance The methods proposed here for virus inactivation encompass spectroscopy (EIS) in a Fe(CN6)4−/Fe(CN6)3− redox system, the use of NPs and nanomaterials known for their intrinsic 6391 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective Figure 4. Schematic of recombinase polymerase amplification-based Citrus tristeza virus detection using gold-nanoparticle-modified DNA strands and electrochemical impedance spectroscopic detection. Reprinted from ref 145. Copyright 2019 American Chemical Society. antipathogenic properties, such as metal-based NPs and could lead to different modes of toxic action for Ag ions and Ag graphene, or for their ability to inactivate viruses, bacteria, NCs toward the viruses that have infected cells. For instance, Ag fungi, or yeasts either photothermally or via photocatalysis- NCs may aggregate in intracellular areas where vital steps of the induced ROS generation. viral cycle are performed, such as protein or genome production SARS-CoV-2 Inactivation by Nano-Based Tools. Silver, or assembly of nucleocapsids before their release into the copper, and zinc show intrinsic antimicrobial properties and are extracellular space, whereas Ag(I) could aggregate in other areas already used in medical equipment and in healthcare settings. of the cells or be rapidly eliminated. Second, the antiviral For instance, Ag is used in wound dressing and in urinary and efficiency of Ag NPs would derive from physical interaction of intravascular catheters. It is advantageous to use NPs composed Ag NPs with the surface of viruses, which would impede their of these metals rather than bulk materials or the metal ions docking on host cells and limit their infectivity. This mechanism themselves because NPs release the toxic metal ions slowly and was demonstrated by Elechiguerra et al. for HIV-1 exposed to 1− progressively right where the antimicrobial action is needed and 10 nm Ag NPs157 and by Orlowski et al. for HSV-2 exposed to because NPs can accumulate within cells without being expelled 13, 33, and 46 nm Ag NPs coated with tannic acid.161 by specialized efflux pumps. The antimicrobial property of Ag Elechiguerra et al. found that the optimal size of Ag NPs was has been used since ancient times for medical applications154 around 10 nm, with larger or smaller NP sizes showing weaker and more recently in commercial products such as silver zeolites physical interaction with the virus. In contrast, Orlowski et al. in paints155 and in food trays156 as biocide. The antiviral found that the larger the NP, the more effective its blocking was efficiency of Ag NPs has been demonstrated in a variety of of virus attachment to host cell. The same mechanism, viruses, including HIV-1,157 monkeypox virus,158 bacterioph- combined with the release of Ag(I), was also proposed by De ages UZ1 and MS2,159,160 murine norovirus MNV1,159,160 Gusseme et al. to explain the reduced infectivity of MNV-1 virus HSV,161 HBV,162 and, recently, in porcine epidemic diarrhea when exposed to 11.2 nm biogenic Ag NPs.159 Finally, this virus (PEDV).163Antiviral properties of Ag NPs arise from three docking of Ag NPs on the surface of viruses could be associated different mechanisms. First, Ag(0) NPs dissolve and release with the local release of ROS from the Ag NP surface, which some toxic Ag(I) forms (including Ag+ ions), which could be would damage the envelope and/or membrane of the virus. Ag responsible for their antiviral activity. As a soft metal, Ag shows NPs are already used in wound dressings, catheters and other strong affinity toward sulfur, and therefore, it interacts strongly medical equipment; their use could also be envisaged to confer with thiols from small molecules such as cysteine or glutathione biocidal properties to paints used in healthcare settings, or to air or with sulfhydryl groups in the active sites of many enzymes. filters or face masks. Ag NPs loaded on filters show effective Ag(I) may interact with surface proteins of viruses or antiviral activity against bacteriophage MS2, which drops with accumulate in host cells and further interact with thiol- dust loading.165 containing enzymes that are involved in virus replication, thus The antimicrobial activity of Cu has also been known since hampering their functions. This hypothesis was proposed by ancient times,166 and surfaces containing a significant amount of Zodrow et al. to explain the antiviral property of Ag NPs for Cu have demonstrated their efficacy to inactivate viruses. bacteriophage MS2 and by De Gusseme et al. in response to Murray et al. showed the efficacy of Cu against poliovirus in MNV-1 exposed to Ag NPs.159,164 Moreover, Ag2S nanoclusters 1979.167 More recently, the efficacy of Cu was demonstrated on (NCs) with diameters of 2.5 and 4 nm showed effective the HuCoV-229E coronavirus; the effectiveness of Cu to inhibition of PEDV replication in Vero cells via inhibition of the inactivate other forms of coronaviruses suggests potential similar synthesis of viral negative-strand RNA and of virus budding from efficacy against SARS-CoV-2.168 Whereas HuCoV-229E persists the cells, but not by preventing their anchorage on cell for more than 6 days in an infectious state on smooth surfaces membranes or their intracellular penetration. Exposing cells to (Teflon, polyvinyl chloride, ceramic tiles, glass, stainless steel), it Ag+ ions at the same concentration did not inhibit virus is inactivated in less than 60 min on brasses containing at least replication, which led the authors to conclude that the antiviral 70% Cu or Cu−Ni alloys containing at least 90% Cu.168 When property of Ag NCs was independent of the release of Ag(I).163 incubated on Cu-containing surfaces, the viral genome becomes However, the mechanisms by which Ag+ ions and Ag NCs enter fragmented, ensuring the irreversibility of inactivation.168 The into cells are different and, consequently, their local distribution proposed inactivation mechanisms include both toxicity toward and handling within cells would also be different. This difference virions of Cu ions released from the Cu-containing surface and 6392 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective attack of viral proteins and lipids by ROS generated from Cu could be offered by other negatively charged, sharp-edged 2D reacting with exogenous hydrogen or molecular oxygen through nanomaterials such as Ti3C2Tx MXene, which has shown Fenton-like or Haber Weiss reactions.166 Likewise, both SARS- promising bacterial inactivation effects against both Gram- CoV-1 and SARS-CoV-2 are inactivated on Cu surfaces in less positive and Gram-negative species due to similar hypothesized than 4 h, whereas they persist for 48−72 h on plastic and mechanisms.118,183 stainless steel and less than 24 h on cardboard.153 In this case, Graphene derivatives linked to virus-specific antibodies have the main inactivation mechanism is also proposed to be damage also been adopted in antiviral platforms based on antibody- to viral proteins and lipids by Cu ions and ROS, in particular, mediated binding and sensing mechanisms, which have been envelope proteins.153 Using Cu brasses or Cu-containing alloys shown to capture a number of viral species successfully including rather than stainless steel would provide effective antimicrobial rotavirus, avian influenza virus subtypes H5 (AIV H5) and H7 surfaces (doorknobs, bed rails, etc.) in healthcare settings. (AIV H7), and influenza virus H1N1.184−187 Supported catalysts composed of Al2O3 impregnated with Ag Photothermal Inactivation of SARS-CoV-2. Another and Cu to form Ag/Al2O3 (5% Ag) and Cu/Al2O3 (10% Cu) example of the use of noble metals for disinfection is the ability also inactivate SARS-CoV virus in less than 5 and 20 min, of Ag and Au NPs and nanorods to induce heating when respectively, which would be useful for air disinfection.169 illuminated at optimal wavelength, corresponding to the plasmon resonance condition, in a process called plasmonic Using Cu brasses or Cu-containing photothermal treatment.188 This property is currently being evaluated by nanomedical researchers as a method for killing alloys rather than stainless steel would cancer cells with Au NPs because Au NPs are considered much provide effective antimicrobial surfaces less toxic than Ag NPs. By tuning NP size and shape, it is possible (doorknobs, bed rails, etc.) in healthcare to emit intense heat under solar irradiation of Au NPs and to settings. inactivate viruses, as demonstrated by Loeb et al. with bacteriophages MS2 and PR772 exposed to Au nanorods and nanocubes or to surfaces coated with such NPs.189 Close contact Cu and CuO NPs have also been shown to release Cu ions between NPs and the pathogen is necessary for the process to be when in contact with live cells.170,171 The large surface that NPs effective, which supposes that NPs adsorb onto their surface. develop due to their small size endows them with a reactivity Elsewhere, Nazari et al. used femtosecond pulsed laser higher than that of their bulk counterpart and would fasten the irradiation on Au nanorods to inactivate murine leukemia kinetics of Cu ion release. The use of nanostructured Cu surfaces virus (MLV).190 Here, inactivation did not require contact would further enhance their antimicrobial activity. Moreover, between Au NRs and viruses, and the addition of ROS these NPs could inactivate viruses if sprayed on contaminated scavengers did not reduce the inactivation effect, suggesting surfaces or loaded onto textile fabrics to confer antimicrobial that neither heat nor ROS generation accounted for the properties (masks, blouses, etc.). Indeed, CuO-impregnated observed effect. The authors propose that the underlying masks have shown remarkable anti-influenza virus (H1N1 and mechanism is plasmon-enhanced shockwave generation, which H9N2) activity under simulated breathing conditions,172 and alters virus membrane and/or surface groups and, therefore, the activity of these materials toward SARS-CoV-2 should be reduces virus binding and fusion with the host cell.190 investigated. The viral disinfectant properties of Ag NPs and Inactivation of SARS-CoV-2 by Photocatalytic Nano- CuO NPs is further enhanced when they are combined with Fe particles. Photocatalytic NPs offer another possible approach as bimetallic particles, due to coupled redox reactions between to the inactivation of SARS-CoV-2. The most described NP in the two metals.173 this category is titanium dioxide (TiO2), which shows In addition to metal NPs, graphene derivatives have also photocatalytic properties when illuminated under UV light, is shown promising viral inactivation properties.174 For example, considered inert, has low toxicity, and is not susceptible to graphene oxide (GO) sheets and sulfated GO derivatives have photocorrosion.191 TiO2 is currently used in paints and been found to be effective against herpes simplex virus type-1 lacquers,155 in self-cleaning windows, and for water purifica- (HSV-1) infections, with viral binding and shielding as the two tion.192 TiO2-containing paints have also been envisaged for putative main inhibitory mechanisms.175 Thermally reduced purifying ambient air because photocatalytic TiO2 successfully graphene oxide (rGO) sheets functionalized with biocompatible removes volatile organic compounds (VOCs) when exposed to hyperbranched polyglycerol (hPG) and then sulfated have also UV light. However, recent findings show that VOC disruption is been generated as graphene-based heparin biomimetics.176−178 associated with the release of toxins in the air, which questions Sulfate-rich polymers like heparan sulfate and its equivalent the prudence of TiO2-doped paints for air purification soluble counterpart heparin are widely known as broad antiviral purposes.155 If effective, the use of TiO2 photocatalysis for agents,179,180 but their use is limited due to their anticoagulant SARS-CoV-2 inactivation would be particularly useful for effects. Sulfated rGO-hPG sheets were found to be effective at surface decontamination using TiO2-doped paints, aerosol inhibiting orthopoxvirus and herpesvirus strains, particularly in decontamination using air filtration filters and ventilation the early stages of the infection, although they could not prevent systems impregnated with TiO2 that can be exposed to UV cell-to-cell spread. Additional antiviral activity of graphene light, and for wastewater treatment. derivatives has been attributed to the negative surface charges The underlying mechanism of this photocatalytic process and sharp edges of the individualized sheets, as the electrostatic relies on the excitation of an electron from the valence band interactions promote binding with the positively charged virus (VB) of the photocatalytic material to the conduction band particles. Negative charges on sharp-edged single-sheet GO and (CB) when exposed to UV light, which leaves a positive hole rGO were shown to bind and to suppress the infection of (h+) in the VB. The e−/h+ charge carriers migrate to the surface pseudorabies, PEDV, EV71, and H9N2 viruses.181,182 This of the photocatalyst and initiate reactions leading to the mechanism suggests that potentially similar antiviral effects production of ROS, including the superoxide anion, hydrogen 6393 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective Figure 5. Droplets and droplet nuclei as important mechanism for transmission of infection. Liquid droplets containing SARS-CoV-2 virions originating from the respiratory tract of infected patients are emitted into the air and carry other materials including bacterial cells and epithelial cells. They are reduced in size by evaporation to small, dry particles resulting in droplet nuclei. peroxide, the hydroxyl anion, and hydroxyl radical.193 The The underlying mechanism is thought to combine both production of hydroxyl radicals by the oxidation of water enhanced photoactivity due to the lower band gap of (Ag, molecules on the photocatalysts’ surface accounts for their Cu)-TiO2 than that of TiO2197 and antimicrobial activity of free disinfection activity, owing to their capacity to oxidize many Ag and Cu ions released into the treated water.198 Another organic constituents of microorganisms, such as lipid perox- strategy to improve the antiviral capability of TiO2 is by idation, leading to damage to cell wall and cell membrane, increasing its potential to absorb viruses, which has successfully protein alteration, and/or DNA damage.193 Bare TiO2 exposed been achieved by mixing TiO2 NPs with SiO2 NPs. Due to the to UV light is effective against a broad spectrum of Gram- large specific surface area of SiO2, the mixture of NPs inactivated positive and Gram-negative bacteria, including multi-drug- bacteriophage MS2 more effectively than did TiO2 alone, in resistant strains but also against some fungi, viruses, and yeasts. spite of reduced hydroxyl production.199 Glass slides coated As discussed by Bogdan et al., according to some authors, viruses with TiO2 doped with Pt show slightly better efficiency in would be more susceptible to inactivation than bacteria.194 inactivating aerosols containing influenza A (H3N2) virus than Among viruses, some researchers have found that enveloped do surfaces coated with only TiO2 when irradiated with UV- viruses would be more protected from photocatalytic A,200 owing to their increased oxidizing photocatalytic proper- inactivation than non-enveloped viruses, whereas other authors ties. Finally, as described by Byrnes et al.,193 new photocatalytic reported the opposite.194 Only one article reported the materials that show efficient antibacterial activity have been usefulness of this inactivation strategy for treatment of SARS- developed and could be tested for the inactivation of SARS- CoV, using a photocatalytic titanium apatite filter (PTAF). This CoV-2. These new materials include (among others) BiVO4, filter showed effective inactivation of SARS-CoV when exposed CuFeO 2 , CuY x Fe 2−x O 4 , LaFeO 8 , CuMn 2 O 4 , ZnMn 2 O 4 , for 6 h to UV light.195 One could also imagine that BaCr 2 O 4 , SrCr 2 O 4 , NiCo 2 O 4 , CuCo 2 O 4 , LaCoO 3 , and photocatalysts coupled to UV light could damage spike proteins La0.9Sr0.1CoO3. Importantly, before being used for SARS-CoV- and lead to decreased infectious capacity of the virus. 2 inactivation, their nontoxicity should be ensured. Because TiO2 shows low solar light activity and a high Nanotechnology-Based Solutions to Increase the recombination rate of electron−hole pairs, researchers have Efficiency and Safety of Protective Devices. Cryoelectron developed second-generation photocatalysts in which TiO2 is microscopy (cryo-EM) studies show that SARS-CoV-2 virions used in combination with other components, such as metals. are particles near the larger end of the NP size range (70−90 This new generation of photocatalysts shows high efficiency of nm).21,201 However, when dispersed into the air, the infectious inactivation of a wide range of bacteria and some viruses. Among particles exist as functionally larger particles. Initially, liquid them, S-doped and N-doped TiO2 show photocatalytic droplets containing coronavirus virions originating from the properties when exposed to visible light and, therefore, would respiratory tract of infected patients are emitted during normal possibly be effective under interior lightning. The antimicrobial breathing, forced expiration (e.g., coughing and sneezing), or properties of these photocatalysts have been tested with a variety aerosol-generating medical procedures (e.g., intubation and of bacteria, sometimes indicating good disinfection efficiency suctioning). Liquid droplets emitted into the air through these (for reviews, see refs 192 and 193), but to our knowledge, they mechanisms originate from points throughout the respiratory have not been tested on viruses. Moreover, depositing some Ag tract and carry within them virions as well as other materials NPs on the surface of TiO2 NPs increases their antiviral associated with the airways, including bacterial cells and efficiency against MS2 by means of increased production of epithelial cells (Figure 5). Droplets are emitted over a wide hydroxyl radicals.196 A Ag- and Cu-doped TiO2 nanowire size range, and their potential viral burden is a cubic function of membrane is more active in eliminating bacteriophage MS2 particle diameter (Figure 6). Thus, larger droplets have the from drinking water than are TiO2, Ag-TiO2, or Cu-TiO2 potential to carry a significantly larger burden of virions membranes, both in the dark and when exposed to UV light. according to their size and are substantially more hazardous 6394 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective fibers through which air is moved. Their purpose is to arrest particles as they move through the matrix. Filters capture particles chiefly by three mechanisms: impaction, interception, and diffusion. Impaction occurs when the momentum of a particle propelled toward a filter fiber prevents the particle from diverging around the fiber along the flow lines of the air stream, causing the particle to collide with the fiber. Impaction is the primary mechanism responsible for removing particles greater than 500 nm in diameter. Interception occurs when a particle diverges around a fiber along the flow lines of the airstream, the distance between the vector of the airstream and the centroid of the particle is smaller than the radius of the particle, and the particle touches the fiber. Interception operates efficiently on particles greater than 200 nm in diameter. Diffusion is the final important mechanism of particle removal, and it is most effective Figure 6. Maximum theoretical viral burden versus droplet nucleus at removing very fine particles less than 200 nm, especially at low size (nm). flow rates. Particles around 300 nm in diameter are least subject to these three removal mechanisms, and they are considered the “most penetrating” particles for a majority of filter types.204 than small droplets. Once emitted into the air, water from When virus-laden droplet nuclei are deposited on filter media, droplets immediately begins to evaporate. Water loss is they penetrate the filter matrix to different depths depending on associated with a rapid decrease in both particle diameter and their size characteristics: larger particles tend to become terminal settling velocity (the equilibrium rate of fall of a particle impacted or intercepted nearer the surface of the intake-facing in still air). The rate of evaporation of the largest droplets (>150 side, whereas smaller particles penetrate more deeply into the μm) is often insufficient to slow their swift descent in air, and fibrous matrix. In the case of filtering facepiece masks, cyclical they impact on nearby surfaces. However, the rapid water loss breathing can cause changes in the physical characteristics of and sharp slowing of settling velocity of smaller droplets enables particles after they have been deposited. Humid exhaled air them to avoid a similar fate. Their constituent solid residues are causes hygroscopic droplet nuclei to swell, becoming larger than instead drawn together during evaporation and cemented with they were when captured on filtration media. This size change dried respiratory secretions, and they remain aloft as droplet nuclei. Several epidemiological studies have supported the From the standpoint of COVID-19, potential for droplet nuclei to be an important means of transmission for SARS-CoV-2.202,203 there are many opportunities for Assuming a median virion size of about 100 nm, a droplet nanotechnology-based solutions to in- nucleus of 1 μm diameter could contain up to 370 randomly crease the efficiency and safety of air packed virions. A similar 10 μm diameter droplet nucleus could filter and mask devices. contain up to 360,000. In practical terms, however, the size- defining element of a droplet nucleus is determined by the component item with the largest volume, which is often a can affect the ability of the filter fibers to retain particles and can bacterial cell or an epithelial cell. Thus, droplet nuclei in the 1− lead to redistribution, shedding, or even breakthrough of 10 μm size range and above contain far fewer virions than this particles. theoretical maximum. From the standpoint of COVID-19, there are many Filter media, such as those used in N95 masks and in opportunities for nanotechnology-based solutions to increase mechanical ventilation systems, consist of myriad interwoven the efficiency and safety of air filter and mask devices. Some Figure 7. Scanning electron microscope images of electrospun nanofibers on polypropylene filter fabric (a) and titania-coated electrospun nylon nanofibers (b). Reprinted with permission from ref 206. Copyright 2010 Springer Nature. 6395 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective specific opportunities include (i) improving particle capture and aim of using it as a platform material for viral helicase retention characteristics, particularly, in the 300 nm diameter inhibition.211 size range; (ii) reducing the effects of exhaled humid air on Initial studies were performed with hepatitis C virus (HCV) particle redistribution; (iii) rapid inactivation of membrane- NS3212 helicase activity and severe acute respiratory syndrome bound microbes including enveloped viruses upon capture; and coronavirus (SARS-CoV).211 These studies were enabled by the (iv) thin, high-efficiency filtration media for personal masks that evidence that single-stranded nucleic acids can adhere to the are able to be reused repeatedly without loss of efficiency (e.g., surface of GO through π−π stacking interactions between the novel electrospun nanofibers). In this context, recent findings hexagonal graphitic units of GO and the nucleotides. Beyond exploring the performance of several fabrics commonly used in therapeutics and diagnostics, graphene is also being pursued as cloth masks, alone or in combination, suggest that the combined an “engineering” material to enhance the barrier properties of mechanical and electrostatic effect observed in hybrids enabled masks, gloves, and gowns for medics against bacteria and viruses enhanced performance with a filtration efficiency >80 and >90% larger than 300 nm.213 Contrastingly, MoS2 nanosheets could be for particle sizes <300 and >300 nm, respectively.205 employed as a novel class of 2D nanocarriers functionalized with Electrospinning is a technique that is widely used to produce a variety of therapeutic and disinfection molecules.214 They have nanofibers with diameters smaller than a micrometer (typically, demonstrated a loading capacity much higher than that of ∼100 nm). Even a micron-thin layer of nanofibers can capture nanographenes and Au nanomaterials along with excellent the smallest droplets containing viruses and bacteria and prevent physiological stability. Another advantage of several TMDCs is them from traveling through the mask. TiO2-coated nanofibers their ability to absorb light efficiently (more so than GO) in the deposited on a filter surface by the electrospinning process can near-IR region, with relatively deep penetrability into tissues and capture submicrometer droplets and destroy the virus upon UV minimal phototoxicity, thus enabling different chemophoto- irradiation or under natural sunlight. After a micrometer-thick thermal treatments.215 film of polyamide 11 nanofibers was deposited on polypropylene filter fabric, TiO2 NPs were directly electrosprayed onto the Beyond therapeutics and diagnostics, nanofibers.206 Scanning electron microscopy (Figure 7) demonstrated that nanofibers were uniformly coated by TiO2 graphene is also being pursued as an NPs without agglomeration. TiO2-coated filters showed “engineering” material to enhance the excellent photocatalytic and bactericidal activity and photo- barrier properties of masks, gloves, and induced hydrophilicity. gowns for medics against bacteria and EMERGING NANOMATERIALS FOR THE FIGHT OF viruses larger than 300 nm. COVID-19 To prevent SARS-CoV-2 spread, proper PPE is critical for Although 2D materials are mostly known in their planar sheet healthcare workers and the general public alike. Moreover, the configuration, they can also form different morphologies such as development of face masks and other protective materials that nanoflowers, offering a very high surface area accessible to the can not only capture the aerosol droplets but also immobilize virus. The petals are atomically thin, radiating from a common and kill the virus would be a major step toward preventing the core and their dimensions can vary from tens of nanometers to spreading of COVID-19 and other infectious diseases. New about a micron. Atomically thin TMDCsWSe2,216 WS2,217 nanomaterials can help to accomplish this function such as MoSe2,218 and MoS2219 have been obtained in this loading Ag NPs on these materials because they show effective morphology when synthesized from chemical precursors in antiviral activity against bacteriophage MS2 when loaded on liquid phase at moderate temperatures (up to 300 °C). The filter surfaces.165 syntheses are scalable, and the fact that they are directly grown and not exfoliated from bulk as 2D nanocrystals has the The development of face masks and advantage of controlling the chemistry and crystal phase (from other protective materials that can not 2H to 1T). This emerging variability of morphology of TDMCs is now only capture the aerosol droplets but attracting interest due to their high surface areas and edge also immobilize and kill the virus would reactivity. The high density of edges with dangling bonds be a major step toward preventing the underscores their ability to be readily functionalized with NPs and molecules. In addition, S and Se termination of the basal spreading of COVID-19 and other plane and edges can be particularly favorable to anchor infectious diseases. biologically relevant molecules. Nanoflowers of TMDCs present attracting properties in nanomedicine applications because they Graphene and Transition Metal Dichalcogenides. could host a large number of molecules and NPs on their edges Graphene and layered transition metal dichalcogenides and thus can develop abilities to detect and to inactivate (TMDCs) have attracted enormous attention in the area of pathogens, to deliver molecules, and to interfere with cellular biomedical applications for diagnostics, therapeutics, safety/ functioning.220 Their stability in air and their availability as free- security, and environmental monitoring. Whereas pristine standing nanomaterials in addition to their strong substrate graphene has seen applications in biosensors devices, its anchoring make them suitable for use in different environments derivative GO underwent a wealth of investigation for rapid such as in aerosols, on surfaces, in face masks, etc., to detect and/ detection, disinfection of pathogens, and enzyme assays, or to inactivate the virus. becoming a platform material for a variety of biomedical Two-Dimensional Carbides and Nitrides (MXenes). applications.207−209 A decade ago, studies started to emerge Among the emerging materials, MXenes are particularly where GO was employed for enzyme activity assays,210 with the promising for the development of coatings that are capable of 6396 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective capturing and inactivating viruses for use on face masks and RETHINKING THE FUTURE: ONE HEALTH, other PPE. CONTAMINATIONS OF KNOWLEDGE, AND MXenes are hydrophilic and they carry high negative charge NANOTECHNOLOGY (zeta-potential in solution is between −30 and −80 mV). As The COVID-19 global emergency is making humans face such, Ti3C2Tx MXene has been shown to adsorb amino acids unprecedented challenges. This new social scenario is strongly221 and may be able to bind strongly to viral spike necessitating collective thought as to where our actions are peplomers and to immobilize the virus, thus deactivating it. It interconnected and interdependent, going beyond boundaries performs analogously to a strong magnet for proteins. and cultural heterogeneity. The common interest, in the name of Furthermore, MXenes have been shown to be photocatalytically health as our primary need, must be addressed in the future active, meaning that once a virus is adsorbed onto the surface, it having in mind the “One Health” concept,237 relying on will be possible to apply light to degrade the adsorbate evidence that the well-being of humans is strictly interconnected simultaneously.222−224 MXenes are among the most efficient with that of animals and the environment. light-to-heat converters due to their plasmon resonance in the To address such a complex challenge, cooperation among visible or IR range. For example, Ti3C2Tx is excited by red light diverse researchers with complementary expertise is required. (780 nm plasmon resonance) and can be sterilized using a red/ The present challenge should be taken as an incredible infrared lamp as well as solar light if the virus survives on the opportunity to remind our globalized world that, as shown for contact with the surface. A wide variety of MXenesincluding other scientific contexts, multi- and interdisciplinary method- Ti3C2Tx, Ta4C3Tx, Nb2CTx, and othersare biocompat- ology involving transversal disciplines, promoting the exchange ible.225−229 At the same time, some MXenes have shown of knowledge among countries, and increasing diversity in teams antibacterial properties, likely due to the combination of their all will be essential to achieve new and critical scientific charge transfer ability and hydrophilicity.183,230,231 Further- solutions.238 more, it has been shown that the most common and least In this view, nanotechnology is inherently a field in which expensive titanium carbide MXenes have no negative ecological scientists with incredible diverse backgrounds have converged in or toxicological impact on the environment.232 Nanometer-thin fruitful cooperations for multifaceted problems. Today more coatings of single-layer MXene flakes on the exposed surfaces are than ever before, nanotechnology is needed to lay new worth exploring. Other new materials, such as metal oxides or foundations toward counteracting the current global public metal−organic frameworks, deserve attention and should be health threat; preparing for possible new challenges, for instance, explored as antiviral materials, as well, because they are also in infectious diseases; and rethinking a more sustainable future capable of releasing disinfectants from their pores. based on science. In addition to the known pulmonary findings, it is estimated that 30−40% of hospitalized COVID-19 patients have evidence AUTHOR INFORMATION of kidney injury, and a significant percentage of those patients Corresponding Authors require renal replacement therapy (RRT) if their kidney Carsten Weiss − Institute of Biological and Chemical Systems, function fails outright.233 Kidney injury is an important Biological Information Processing, Karlsruhe Institute of predictor of mortality among those infected with COVID-19. Technology, 76344 Eggenstein-Leopoldshafen, Germany; Kidney function is essential to life: healthy kidneys filter the Email: carsten.weiss@kit.edu blood of harmful toxins, contribute to bone health, and maintain Marie Carriere − Univ. Grenoble Alpes, CEA, CNRS, IRIG, homeostasis of fluid and electrolytes. SyMMES-CIBEST, F-38000 Grenoble, France; When the kidneys fail, hemodialysis offers a life-sustaining Email: marie.carriere@cea.fr therapy to prevent the buildup of uremic toxins that would Lucia Gemma Delogu − Department of Biomedical Sciences, otherwise result in death.234 To perform hemodialysis, the University of Padua, 35122 Padova, Italy; orcid.org/0000- patient’s blood is passed through a filtration circuit that contains 0002-2329-7260; Email: luciagemma.delogu@unipd.it a semipermeable membrane (“dialyzer”). On the other side of the membrane, a balanced fluid (“dialysate”) travels in the Authors opposite direction to the patient’s blood, dragging toxins and Laura Fusco − Cancer Research Department, Sidra Medicine, excess electrolytes across the membrane from blood into Doha, Qatar; Department of Chemical and Pharmaceutical dialysate across their concentration gradients. The filtered Sciences, University of Trieste, 34127 Trieste, Italy blood is returned to the patient and the dialysate, once it passes Ilaria Capua − One Health Center of Excellence, University of through the filter, is discarded. Novel efficient sorbents for Florida, Gainesville, Florida 32611, United States uremic toxins are critically needed to improve the efficiency of Jose Angel Regla-Nava − Division of Inflammation Biology, La current technology, as well as to enable the development of Jolla Institute for Allergy and Immunology, La Jolla, California wearable and portable dialysis technologies that could be critical 92037, United States to the care of COVID-19 patients. MXenes can regenerate Matteo Pasquali − Department of Chemical & Biomolecular dialysate by removing toxins that build up in the setting of Engineering, Department of Chemistry, and Department of kidney failure. Preliminary research demonstrates that Ti3C2 Materials Science and Nanoengineering, Rice University, Houston, MXene is biocompatible and selectively adsorbs urea, a uremic Texas 77251, United States; orcid.org/0000-0001-5951- toxin that is otherwise difficult to eliminate from dialysate, due to 395X the presence of narrow slit pores between the negatively charged James A. Scott − Dalla Lana School of Public Health, University MXene sheets.235 Thus, MXenes may be able to address key of Toronto, M5T 1R4 Toronto, Ontario, Canada limitations of current ambulatory dialysis systems by offering Flavia Vitale − Department of Neurology, Bioengineering, Physical efficient urea adsorption, small size, and light weight.235 Experts Medicine & Rehabilitation, Center for Neuroengineering and have posited that MXenes might be a key technology in Therapeutics, University of Pennsylvania, Philadelphia, revolutionizing RRT delivery.236 Pennsylvania 19104, United States; Center for Neurotrauma, 6397 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective Neurodegeneration, and Restoration, Corporal Michael J. and characterization of the physico-chemistry and fate of nanomateri- Crescenz Veterans Affairs Medical Center, Philadelphia, als. Pennsylvania 19104, United States Laura Fusco received her B.Sc. in Medical Biotechnologies from the Mehmet Altay Unal − Stem Cell Institute, Ankara University, University of Milan (Italy) studying the effects of airborne particulate Ankara 06100, Turkey; orcid.org/0000-0001-8607-5043 matter on human health. After receiving her M.Sc. in Medical Cecilia Mattevi − Department of Materials, Imperial College Biotechnologies and Molecular Medicine from the University of London, London SW7 2AZ, United Kingdom; orcid.org/ Trieste (Italy), in 2018, she earned her Ph.D. in Chemistry from the 0000-0003-0005-0633 same university (Prof. Maurizio Prato), with a project on the Davide Bedognetti − Cancer Research Department, Sidra toxicological effects of graphene and graphene-based materials at the Medicine, Doha, Qatar skin level, supported by the European Union H2020 Programme, Arben Merkoçi − Nanobioelectronics & Biosensors Group, integrating her research at the Karolinska Institutet (Prof. Bengt Catalan Institute of Nanoscience and Nanotechnology (ICN2), Fadeel), Sweden. Currently, she is Visiting Scientist at Sidra Medicine CSIC and BIST, 08193 Bellaterra, Spain; ICREA - Institució (Qatar) in the framework of the CARBOIMMAP H2020-MSCA-RISE Catalana de Recerca i Estudis Avançats, ES-08010 Barcelona, project (L.G. Delogu coordinator) concerning the immune interactions Spain; orcid.org/0000-0003-2486-8085 of carbon nanomaterials. In the context of COVID-19, she studies the Ennio Tasciotti − Orthopedics and Sports Medicine, Houston potential antiviral properties of various nanomaterials as well as the role Methodist Hospital, Houston, Texas 77030, United States; of airborne particulate matter on the outbreak. Department of Plastic Surgery, MD Anderson, Houston, Texas 77230, United States; orcid.org/0000-0003-1187-3205 Ilaria Capua is Full Professor and Director of the One Health Center of Açelya Yilmazer − Stem Cell Institute and Department of Excellence at the University of Florida (United States). She is a Biomedical Engineering, Faculty of Engineering, Ankara virologist, known the world over for her ground-breaking research on University, Ankara 06100, Turkey; orcid.org/0000-0003- influenza viruses, particularly avian influenza and for pioneering the 2712-7450 open access concept in Science. She also was a Member of the Italian Yury Gogotsi − A.J. Drexel Nanomaterials Institute, and Parliament for over three years (2013−2016). She has authored over Materials Science and Engineering Department, Drexel 220 scientific publications in peer-reviewed journals and has published University, Philadelphia, Pennsylvania 19104, United States; scientific books on Avian Influenza and Newcastle disease as well as four orcid.org/0000-0001-9423-4032 books for the general public. She has obtained several awards including Francesco Stellacci − Institute of Materials, Ecole Polytechnique the Penn Vet World Leadership in Animal Health Award. She is active Federale de Lausanne (EPFL), 1015 Lausanne, Switzerland; in the field of science communication and in promoting female Interfaculty Bioengineering Institute, Ecole Polytechnique Fédérale leadership in the scientific arena. She regularly contributes columns and de Lausanne (EPFL), 1015 Lausanne, Switzerland; editorials to mainstream Italian press. Her research interests are related orcid.org/0000-0003-4635-6080 to the study of new approaches in infection disease in animals and Complete contact information is available at: humans. https://pubs.acs.org/10.1021/acsnano.0c03697 Jose Angel Regla-Nava is a Postdoctoral Fellow at the La Jolla Institute, San Diego (United States). His research projects are mainly focused on Author Contributions the Dengue and Zika viruses. He graduated from Universidad de # Guadalajara (Mexico) with a B.Sc. degree in Chemistry Pharmaceutical C.W., M.C., and L.F. contributed equally to this work. and Biology. He then obtained is M.Sc. in Molecular and Cellular Notes Biology in 2010 and a Ph.D. in Biochemistry, Molecular Biology, The authors declare no competing financial interest. Biomedicine, and Biotechnology (Molecular Bioscience) in 2015 from Biographies the Universidad Autonoma de Madrid, Spain. His Ph.D. work focused Carsten Weiss is a Principal Investigator at the Institute of Biological on the study of the identification of the Mechanisms Causing Reversion and Chemical Systems at Karlsruhe Institute of Technology to Virulence in an Attenuated SARS-CoV for the Design of a (Germany). His primary interest and expertise lies in the area of Genetically Stable Vaccine. molecular toxicology, i.e., the interaction of genotoxins and nanoma- Matteo Pasquali is the A. J. Hartsook Professor of Chemical & terials with living systems and the analysis of adverse effects. The group Biomolecular Engineering, Chemistry, and Materials Science & investigates different nanomaterials and groups of chemicals (PAHs, NanoEngineering at Rice University, where he also serves as Chair of dioxins, mycotoxins, metals, cytostatic drugs, etc.) in various cell culture the Chemistry Department, Houston (United States). He has been systems, zebrafish, and mice. A special emphasis of his research is on the recognized by numerous awards in the field and also founded two mechanisms of toxicity relevant for cytotoxicity and inflammation. companies, DexMat (smart carbon nanotube, CNT, materials) and Marie Carriere is a Principal Investigator in the Molecular systems and NanoLinea (medical applications of CNT fibers). His laboratory is a nanomaterials for energy and health laboratory at Commissariat à key center for the scalable manufacturing and application of carbon l’Energie Atomique et aux Energies Alternatives (CEA), in Grenoble nanotubes and graphene-based materials with enhanced mechanical, (France). Her primary research interests are the toxicity and ecotoxicity electrical and thermal properties. His research targets applications in of nanomaterials, environmental pollutants, and food additives. In this wearables, energy transmission and harvesting, biomedicine, aerospace, context, her studies are focused on DNA damage and repair, from and defense. damage recognition and the development of analytical techniques to James A. Scott is Full Professor the Department of Public Health detect and to quantify them with the highest sensitivity and selectivity, Sciences and the Gage Occupational & Environmental Health Unit and to genotoxicity assessment. A multidisciplinary approach is used, going the Director of the UAMH Centre for Global Microfungal Biodiversity, from classical toxicity testing to medium-scale and high-content a world-class repository of medically and environmentally important, analysis and -omics approaches coupled with state-of-the-art micros- living microfungi, Toronto (Canada). Dr. Scott also coleads copy and analytical techniques, including synchrotron-based methods SyMBIOTA, a large, CIHR-funded, multidisciplinary team studying 6398 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective the impact of perinatal environmental exposures on early life atopy and GraphenicaLab and PaperDrop Diagnostics, the last one also working asthma in response to perturbations of the developing human gut on COVID-19 diagnostics with paper-based nanobiosensors. microbiome. He also leads an Alfred P. Sloan Foundation project on Ennio Tasciotti founded and directed the Center for Biomimetic microbiology of the built environment. His research bridges occupa- Medicine and Musculoskeletal Regeneration as an Associate Professor tional health and environmental health, focusing on the measurement of Nanomedicine and Orthopedic Surgery at the Institute for Academic of exposure to health-relevant biological contaminants, particularly, Medicine. Sequently, he served as Director of the Center for bioaerosols. Musculoskeletal Regeneration as Full Professor of Regenerative Flavia Vitale is an Assistant Professor in the Department of Neurology, Medicine. He has wide expertise in applied science and translational Bioengineering and Physical Medicine and Rehabilitation at the research and a background in biology, biotechnology, and molecular University of Pennsylvania (United States). She received her Ph.D. in medicine. His main research interests rely on nanotechnology, drug Chemical Engineering at the Università di Roma “La Sapienza” (Italy), delivery, tissue engineering, and regenerative medicine. He is then completed her training in the Department of Chemical and particularly interested in the development of new lines of research at Biomolecular Engineering at Rice University (United States) in 2015, the cross field of medicine and nanobiotechnology. where she was a R. A. Welch Foundation Postdoctoral Fellow. Dr. Açelya Yilmazer is an Associate Professor at the Department of Vitale has received a number of awards, including the Graduate Biomedical Engineering at Ankara University (Turkey). In 2012, she Research Fellowship, University of Rome “La Sapienza”, the Taking obtained her Ph.D. in the Nanomedicine Lab based in the School of Flight Award from CURE and the McCabe Fellow Award. Dr. Vitale Pharmacy, University College London (Prof. K. Kostarelos). Later, she research focuses on application of carbon nanostructures and MXenes continued her postdoctoral work in the same lab on in vivo cell to bioelectronic interfaces and biosensors. reprogramming. She has extensive experience on in vitro and in vivo Mehmet Altay Unal received his bachelor degree (2003) and M.S. preclinical evaluation of nanomaterials. She has coordinated the (2006) from Ankara University Physics Engineering, Turkey, and Ph.D. genotoxicity related work package of the Graphene Flagera project “G- (2016) degrees from the Ankara University Biotechnology Institute. He IMMUNOMICS”. She was selected as the “Best Young Investigator” in worked at the Department of Biomedical Engineering of Florida Turkey by the Turkish Society of Medical Biology and Genetics in 2013 Institute of Technology, United States (2014−2015). Between 2011 and given the “Young Scientist Award” by the Turkish Academy of and 2018, he worked at the Ankara University Department of Physical Sciences in 2019. Her research group is focusing on the use of Engineering as a lecturer. He is currently lecturer at the Stem Cell nanomaterials and cell reprogramming technologies in cancer and Institute since March 2018. Dr. Unal’s research mainly focuses on the regenerative medicine. She is currently involved in drug repurposing development of cheap, next -generation biosensor devices, under- project for COVID-19 in Turkey, and she is coordinating the standing protein dynamics and protein−ligand interaction, and workpackage related to preclinical investigation of the screened drugs. developing new drug molecules. He is leading a drug repurposing Yury Gogotsi is Distinguished University Professor and Charles T. and project for COVID-19 in Turkey, which aims to screen drugs in silico. Ruth M. Bach Professor of Materials Science and Engineering at Drexel Cecilia Mattevi is an Associate Professor and Royal Society University University. He also serves as Director of the A.J. Drexel Nanomaterials Research Fellow in the Department of Materials at Imperial College Institute. He received his M.S. (1984) and Ph.D. (1986) from Kiev London (United Kingdom) since October 2012. Cecilia is a Fellow of Polytechnic and a D.Sc. degree from the Ukrainian Academy of the Royal Society of Chemistry, and she has been awarded an ERC- Sciences in 1995. His research group works on 2D carbides, Consolidator Grant 2018 on 3D printing of nanomaterial inks for on- nanostructured carbons, and other nanomaterials for energy, water, chip applications. Mattevi’s group focuses on the precise synthesis of and biomedical applications. He has received numerous national and novel atomically thin 2D materials and their three-dimensional international awards for his research and has been elected a Fellow of structuring via 3D printing in the form of miniaturized devices to many professional societies, including the World Academy of Ceramics address pressing challenges in energy storage, energy conversion, and and the European Academy of Sciences. He is an Associate Editor at biomedical applications. ACS Nano. Davide Bedognetti is the Director of the Cancer Research Department Francesco Stellacci is a Full Professor leading the Supramolecular at Sidra Medicine (Qatar). Dr. Bedognetti received his M.D. and Ph.D. Nanomaterials and interfaces laboratory at the Ecole Polytechnique in Clinical and Experimental Oncology and Hematology from the Federale de Lausanne (EPFL), Lausanne, (Switzerland). He is a University of Genoa (Italy). After completing his medical residency in materials scientist with a postdoctoral experience in Chemistry at the Medical Oncology, he joined the Infectious Disease and Immunoge- University of Arizona where he worked with Prof. Joe Perry. He started netics Section (IDIS) of the U.S. National Institutes of Health (NIH), his academic career as a faculty member at the Massachusetts Institute where he completed his postdoctoral fellowship. Dr. Bedognetti’s team of Technology and then moved as a full professor at the Ecole employs high-throughput approaches to deconvolute the molecular Polytechnique Fédérale de Lausanne always in the materials science network of host-tumor interactions, and to understand its relationship departments. Stellacci has published more than 100 papers and has with treatment effectiveness. more than 15 patent applications. His interests are in solid−liquid Arben Merkoçi is ICREA Professor and director of Nanobioelectronics interfaces, supramolecular chemistry, and nanotechnology. His group and Biosensors Group at Catalan Institute of Nanoscience and tries to use the tools of supramolecular chemistry to create Nanotechnology (ICN2) in Barcelona (Spain). He is interested in nanomaterials that have unique properties. The main fields of the design and application of nanobiosensors based on the use of applications are health and environment. nanotechnology and nanomaterials for several applications with interest Lucia Gemma Delogu is an Assistant Professor of Biochemistry at the for diagnostics, environment, safety, and security. His team is University of Padua, Italy. She is a biochemist with postdoctoral developing nanobiosensing platforms including paper-based nano- experience in immunology and material science obtained at the biosensors that, given their efficiency and low cost, are considered to be University of Southern California, Los Angeles. She has been the of special interest for point-of-care diagnostics of various diseases Scientific Coordinator of two interdisciplinary European projects on including COVID-19. He is cofounder of two spinoff companies, nanomedicine and immune interactions of nanomaterials. In this field, 6399 https://dx.doi.org/10.1021/acsnano.0c03697 ACS Nano 2020, 14, 6383−6406 ACS Nano www.acsnano.org Perspective she has received several awards, including the “Marie S. Curie 20Age Groups in 1990 and 2010: A Systematic Analysis for the Global Individual Fellow” under Horizon 2020 from the European Burden of Disease Study 2010. Lancet 2012, 380, 2095−2128. Commission, the “200 Young Best Talents of Italy 2011” from the (8) Watkins, K. Emerging Infectious Diseases: A Review. Curr. Emerg. Italian Ministry of Youth, and “Bedside to Bench & Back Award” from Hosp. Med. Rep. 2018, 6, 86−93. the National Institutes of Health, United States. She pioneered the use (9) The Top 10 Causes of Death. https://www.who.int/news-room/ fact-sheets/detail/the-top-10-causes-of-death (accessed 2020-05-03). of high-dimensional single cell approaches in the context of carbon- (10) Gorbalenya, A. E.; Baker, S. C.; Baric, R. S.; de Groot, R. J.; based nanomaterials and proposed the “nanoimmunity-by-design” Drosten, C.; Gulyaeva, A. A.; Haagmans, B. L.; Lauber, C.; Leontovich, concept. Her research focuses on the immune interactions of A. M.; Neuman, B. W.; Penzar, D.; Perlman, S.; Poon, L. L. M.; nanomaterials, NPs, and air pollution particulate matter. In the context Samborskiy, D. V.; Sidorov, I. A.; Sola, I.; Ziebuhr, J. Coronaviridae of COVID-19, she studies the potential antiviral properties of various Study Group of the International Committee on Taxonomy of Viruses. nanomaterials, as well as the role of airborne particulate matter on the The Species Severe Acute Respiratory Syndrome-Related Coronavirus: outbreak. Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020, 5, 536−544. ACKNOWLEDGMENTS (11) WHO report-98, Johns Hopkins University. www.coronavirus. jhu.edu/map.html (accessed 2020-05-19). L.G.D. acknowledges the European Union’s Horizon 2020 (12) Lovato, A.; de Filippis, C. Clinical Presentation of COVID-19: A research and innovation programme under the Marie Systematic Review Focusing on Upper Airway Symptoms. Ear Nose Skłodowska-Curie Grant Agreement No. 734381 (CARBO- Throat J. 2020, No. 014556132092076. immap), and the University of Padua (Italy) DOR-2020. A.Y. is (13) Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; thankful to the Turkish Academy of Sciences (TUBA) for Fan, G.; Xu, J.; Gu, X.; Cheng, Z.; Yu, T.; Xia, J.; Wei, Y.; Wu, W.; Xie, financial support under the young investigator programme. A.M. X.; Yin, W.; Li, H.; Liu, M.; Xiao, Y.; et al. Clinical Features of Patients thanks funding by the CERCA programme/Generalitat de Infected with 2019 Novel Coronavirus in Wuhan, China. Lancet 2020, Catalunya and the Severo Ochoa Centres of Excellence 395, 497−506. (14) Lauer, S. A.; Grantz, K. H.; Bi, Q.; Jones, F. K.; Zheng, Q.; programme and by the Spanish Research Agency (AEI, Grant Meredith, H. R.; Azman, A. S.; Reich, N. G.; Lessler, J. The Incubation No. SEV-2017-0706) given to ICN2. C.M. would like to Period of Coronavirus Disease 2019 (COVID-19) from Publicly acknowledge the award of funding from the European Research Reported Confirmed Cases: Estimation and Application. Ann. Intern. 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