1

Emerging viral infections

In the past few decades, viral infection outbreaks such as Middle East respiratory syndrome coronavirus (MERS-CoV), H1N1 influenza virus, Ebola virus disease, Zika virus infection and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have imposed substantial morbidity and mortality. The socioeconomic impact is worrisome as the infections could require hospitalization with high direct medical costs as well as absenteeism from work or school.

Healthcare professionals are at risk of infection as viral diseases are disseminated from person-to-person in hospital and family settings [ ]. Dentists have been suggested to be within the class of workers with high risk of Coronavirus disease 2019 (COVID-19) contamination due to both high proximity to individuals and exposure to disease [ ]. Several scenarios for transmission of COVID-19 and other viruses are predictable and include transmission by droplets from talking, coughing, sneezing, and potentially from aerosols produced during clinical procedures [ , ]. The droplets can spread viruses to nearby subjects but long-distance airborne spread is also predicted [ , ].

Several viruses can be isolated from saliva such as cytomegalovirus, Ebola virus, human herpesvirus, herpes simplex virus 2, Influenza virus A, rabies, and tobacco mosaic virus (more information in Ref. [ ]). More recently, Zika peptides and SARS-CoV-2 have been identified in saliva [ , ]. The presence of viruses in saliva is especially concerning for dentists since treatments are performed from a short distance from the patient and often related to generation of aerosols and handling of oral fluids and blood [ ].

The risk of acquiring infectious diseases in the dental office is yet to be fully determined but it cannot be neglected [ , ]. In addition to the exposure to infectious agents within the clinics, dentist may become spreaders due to the close proximity with patients and assistants during treatments [ ]. The personal protective equipment (PPE) is the first layer of protection for healthcare workers [ ]. Adjunctive protection namely face shield can further protect the face from direct splashing and spraying of contaminated fluids. However, the face shield does not present a tight seal around the face and cannot fully protect against aerosols invading its lateral edges [ , ]. Unfortunately, there is no strong evidence regarding the effectiveness of face shields against the transmission of viral respiratory diseases [ ]. Although the PPE performs reasonably well in normal situations, the COVID-19 pandemic has exposed very concerning issues like the critical disruption on supply chains leading to shortage of PPE at affected regions [ , ]. While most of the focus has been put on the development of new therapeutics and vaccines, further development in PPE and engineering controls can positively impact the safety of clinicians and patients.

Air contamination increases significantly following dental treatments [ , ] and may contaminate the skin and mucous membranes of the mouth, respiratory passage and eyes [ , , ]. Previsously, Mycobacterium tuberculosis has been found in aerosol particles generated by dental hand piece used on patients with active tuberculosis [ ]. Notably, the air contamination increases significantly during dental aerosol generating procedures (from 12–75 and 216 CFU/m ³ , respectively). This is even more concerning in multichair dental clinics as the aerosols can contaminate inactive treatment areas (42 CFU/m ³ ) [ ]. The aerosols can remain suspended in air for 20–30 min and spread for 60 and 100 cm [ , , ]. Hence, the clinical setting is frequently disinfected with compounds chlorine compounds or diluted isopropyl alcohol. A systematic review has suggested that the disinfection of semi-critical health care products with “alcohol 70%” allows the persistence of microorganisms (bacteria and viruses) on instrument surface even after the disinfection procedure [ ]. Other chemical disinfectants like chlorine compounds can induce corrosiveness to metals or release of toxic gas when mixed with household cleaning agents containing ammonia or acids [ ]. Of note, the effectiveness of these solutions seems to be associated with the mode of application, time of contact and substantivity [ ]. Unfortunately, these substances only exert the biocidal effect on surfaces where they have been spread upon and this may not fully eradicate the risk of subsequent fomite transmission.

Saliva is abundant with nucleases that destabilize microbial membranes and promote fast degradation of RNA [ ]. There are several salivary proteins such as alpha-2-macroglobulin, mucin MUC5B, gp340, histatins 1 and 3 that present antiviral activity based on viral disruption, neutralizing activity and/or salivary proteins aggregation before swallowing [ , ]. Nevertheless, the interactions between saliva and viruses vary considerably and although some viruses have short survival time in saliva [ , ], others are not readily affected and their presence in saliva can be even used to estimate viral systemic load [ ]. The high complexity of viral/saliva interactions can be further illustrated by the controversial roles salivary gp-340 that inhibits neuraminidase activity of Influenza virus A Phil82 strain but not of the PR-8 strain [ ].

Salivary markers for viral infections involve direct detection of specific viral antigens, such as proteins and nucleic acids or host antibodies to viral infections. Thus, the use of saliva for the detection of viral antigens and antibodies may provide a high accuracy point-of-care platform for detection of viral infections. Remarkably, rapid tests using oral fluids can diagnose HIV infection with very high sensitivity and accuracy [ , ]. Nevertheless, early diagnosis of viral dieseases is difficult due to the need for seroconversion and this challenges the detection of asymptomatic carriers that could prevent further contaminations and assure timely treatment. Fortunately, combined antibody platforms can be promising alternatives to detect asymptomatic infected populations as some virus non-structural and structural components ( e.g. RNA, proteins and peptides) could be detected in saliva in early stage of the infection [ , , ].

Diagnostic platforms based on subject self-collecting saliva, can be pivotal to protect healthcare workers and population during outbreaks that are highly contagious. Although the presence of viable SARS-CoV-2 in saliva is known, the potential contributions of clinicians for rapid diagnostics have been largely neglected due to the current needs for specialized equipment, consumables, and skillsets. Unfortunately, the development of ready-to-use diagnostic tools is very challenging and strategies like the detection of specific antibodies to the SARS‐CoV-2 virus can be limited by cross-reactivity against other coronaviruses [ ]. As a result, rare (if any) ready-to-use saliva tests for COVID-19 have been made available for the public in the first eight months from the declaration of the pandemic. Nonetheless, technological developments over time have already allowed dentistry to play an important role in the development of tests for hepatitis B [ ], hepatitis C [ ], Epstein-Barr [ ], herpes [ ], and cytomegalovirus [ ].

Indeed, there is a global concern on the rise and spread of viral diseases. It is common sense that the fight against viruses is a task mainly taken by virologists, geneticists, pharmaceutical researchers, and professionals from public health sector. However, materials science is receiving growing traction in this fight with several opportunities for breakthroughs to address these critical health crises. The objective of this work is to present some of the main mechanisms for interactions between viruses and materials and how properties can be tuned to negatively affect viral adhesion and survivability, decreasing their viability in environmental surfaces and infectivity in clinical settings. This paper also discusses new approaches to oral antiviral delivery materials and the potential of artificial intelligence for improved therapies.

2

Properties affecting adhesion and survivability of viruses on materials

The potential presence of viruses in saliva, throat fluids and sputum render the oropharyngeal system relevant in the dissemination of viral infections. There is growing concern that aerosols generated by dental procedures performed with high-speed handpiece or ultrasonic instruments can be a source of interpersonal transmissions. A recent study that evaluated the stability of SARS-CoV-2 and SARS-CoV-1 in aerosols and on various surfaces suggested that SARS-CoV-2 was stable and viable on stainless steel and plastic up to 72 h [ ]. Despite the inherent limitations of this study, like the apparatus design used to generate the aerosol and limited translation potential of those findings to clinical settings, this work sheds a light on the role of aerosol and surfaces on virus viability. Likewise, previous studies have shown that SARS-CoV, MERS-CoV and Influenza A virus have the ability to survive on dry surfaces for a duration suitable to facilitate further transmission [ ]. Recently, a group of researchers confirmed the presence of SARS-CoV-2 in air outlet fans, sink, door handle, and other sites from the environment around an infected patient [ ]. As several of these materials are routinely found in dental clinics and hospitals, there are concerns that transmission can occur from human contact with infected surfaces or fomite transmission due to prolonged environmental presence of viruses.

Understanding the mechanism of viral adsorption and adhesion is crucial for the development of materials and coatings with antiviral properties. It is known that the availability of viruses on surfaces depends on the nature of the materials they are spread upon. For instance, the adhesion forces of Aichi virus with polyvinyl chloride is five times greater than those measured on glass [ ]. In this regard, characteristics (isoelectric point, electrical charge, roughness) from the virus and materials are critical for their interactions. Virus particles dispersed in medium present colloidal nature and the surface charge depends on the environmental pH. A review in the results published for 104 viruses has found that the isoelectric points occur in the pH range from 1.9 to 8.4 whereas the most frequent values are in the interval between 3.7 to 7.0. These results indicate that viruses with a very basic isoelectric point (<3.0) are uncommon [ ]. Notably, there is a significant negative relationship between the level of viral adsorption and the isoelectric point [ ], while several viruses in near-isoelectric state can be adsorbed to material bearing surface functional groups like carboxyl, primary amine or quaternary amine [ ]. In fact, the high isoelectric point of cuprous oxide nanoparticles (11.0) has been suggested as a contributing factor for the high interaction capability with viruses [ ]. Notably, the incorporation of copper-based nanoparticles to respiratory protective face masks has provided strong biocidal properties against Influenza A virus [ ]. Hence, it may be feasible to modulate adsorption and survival of viruses on surfaces by knowing their isoelectric point and modulating material surface charge.

Viral adsorption on surfaces is generally considered to be governed by electrostatic interactions and oppositely charged surfaces and viruses usually present extensive adsorption [ , ]. The attraction of viruses dispersed in medium to surfaces can be explained by the classical theories that describe colloidal behaviour including the effects of surface charge in ionic solution and the presence of surrounding counterions. Previous work that evaluated the applicability of the Derjaguin–Landau–Verwey–Overbeek (DLVO) theory to adsorption of poliovirus to metal surfaces has suggested that the double-layer and van der Waals contributions are significant to the total free energy of adsorption [ ]. However, the interactions between virus and surfaces are likely to be governed mainly by long-range electrostatics and shorter-range van der Waals interactions may be less important [ ].

Viral adsorption kinetics onto surfaces need to be taken in consideration when designing materials with antivirus properties. The process of adsorption depends on the rate of virus movement through suspending medium, based upon Brownian motion. Hence, the adsorption is diffusion limited, not affected by mechanical agitation and the amount of virus adsorbed follows a linear function of the square root of time [ ]. Notably, the kinetics of virus absorption are related to the charged state of sorbent surfaces. This can be taken into consideration while designing materials with antivirus properties, since the electrostatic attraction increases when the virion is oppositely charged to the adsorbent surfaces; this predictably results in fast and extensive adsorption [ , ]. Although the viral proteins in an isoelectric state would not strongly repel or attract surfaces, changes in pH can alter such behaviour. In fact, increasing the pH above the virus isoelectric point provides a net negative surface charge to the virions and can significantly enhance their adsorption onto the positively charged material. For instance, MS-2 virions with low isoelectric point of 3.9 have shown almost no adsorption onto negatively charged carboxylated silica with increasing pH. Likewise, poliovirus I has an isoelectric point of 6.6 and does not get adsorbed by negatively charged silica as the environmental pH increases [ ]. This trend has been further confirmed on polymers coated with NH ₂ that presented higher virucidal effects compared with COOH groups against bacteriophage PRD1, which presents an acidic isoelectric point and a net negative charge at pH 7.4 [ ].

In addition, the structure of the viruses also affects adsorption. Enveloped viruses are surrounded by an outer lipid membrane which can strongly adsorb polycations. This interaction has been exploited to create polyethyleneimine coatings containing hydrophobic polycationic chains that after being absorbed can promote envelope disorganization and leakage of the viral genome resulting the viral deactivation [ , ]. Notably, viruses can bind to carbonaceous materials (“universal sorbents”) irrespective of antigenic structure of surface proteins. Nevertheless, the adsorption efficiency to these “universal sorbents” is low and governed through weak van der Waals interactions [ , ]. Finally, steric effects can hinder viral adsorption. These nonbonding interactions can be related to surface irregularities on the sorbent or asymmetries on the virus like protruding protein loops extending from the capsid surfaces which can create unfavourable steric forces hindering close contact of viruses with sorbents weakening the short-ranged van der Walls interactions as shown for MS-2, fr, and GA bacteriophages [ , ].

Material wetting properties may affect virus adsorption and survival. For instance, hydrophobic octadecyltrichlorosilane film had promoted extensively viral disassembly by disrupting the packing of virus coat proteins [ ]. Viruses capsids often present ionizing residues ( e.g. , NH ³⁺ and COO ⁻ , Fig. 1 ) and hydrophobic moieties ( e.g. , propyl group) that can interact with chemical groups from the surfaces of materials and promote physisorption [ ]. Hydrophobic interactions promoting virus particles absorption can be observed on highly oriented pyrolytic graphite (HOPG), which presents nonpolar surface [ ]. For instance, P22 viruses presented higher adsorption on perfluorodecyltriethoxysilane surface, compared with two other sorbents namely triethoxysilane (APTS) and (3-glycidyloxypropyl) trimethoxysilane (GPTS), suggesting that the hydrophobic interactions regulate the virus adsorption at pH of 7.0 [ ]. A previous study has shown negative correlations between viral number and total wax content, and concentrations of fatty acids and alkanes found in vegetables and tomatoes. Notably, the contact angles have been correlated with alkane concentrations, fatty acids and total wax but not with viral adsorption which was more influenced by the three-dimensional arrangement of the superficial wax crystals than by the hydrophobic character of the substrates. This study has also shown that the concurrent analysis of several physiochemical properties ( e.g. , chemical composition, roughness and contact angle) accounts for only 60% of the variations in viral adsorption [ ]. Hence, wetting properties cannot be used in isolation to predict the susceptibility to virus adsorption on materials but shall be considered in combination with other properties to enhance materials antiviral potential.

A to C. Arrangement of functional groups on coat protein segments of different viruses in neutral pH. The coat protein from virion with an IEP in the acid regime present more deprotonated carboxyl groups (A) whereas a virion with IEP at neutral pH will have the negatively charged groups balanced out by a relative higher number of protonated amino groups (B). The binding of hydrogen phosphate to the oxygen atoms on the coat protein shown in B, causes a water chemistry-dependent IEP alteration. This surface complexation neutralizes the positive charge and decreases the IEP of the virion (C). D to F. Protein residue maps at the different symmetries of the P22 virus facets (D) edges (E) and pentons (F). The of percentages of hydrophobic and polar features exposed are shown in green and red. (G) The human saliva can be the source of spread or a diagnostic tool of several viruses (panels A to G were adapted with permission from Refs. [ , ]).

Material roughness may also affect the adsorption and adhesion of viruses but has been mostly neglected, possibly due to the difficulty of producing surface features controlled at a nanometric scale, a spatial resolution required considering the small diameter of viruses like F-specific RNA bacteriophages (20–30 nm) and SARS-CoV-2 (60–140 nm) [ ]. The roughness of materials can influence the virus adsorption since surface features (peaks or depressions) can affect the electric double layer surface structure and the electrostatic interaction energy profile between the colloidal particle and the absorbent. On nanometric scale, the size of the particles have little effect on adhesion when they are smaller than the dominant surface feature as the adhesion will be mostly governed by the geometrical effects of the surface/particle interactions [ ]. Previous work has shown that the phage adhesion on glass with a mean square average of the surface profile (RMS) of 5 nm is weaker than on polypropylene and stainless steel substrates with RMS of 25 and 250 nm, respectively. Interestingly, the surface concentration of adhered Qβ, GA or MS2 phages was lower on glass compared with stainless steel regardless of both materials presenting similar hydrophobicity (5% and 20% equivalent −CH ₃ surface fraction). However, the increase in adhesion forces does not follow a linear trend with surface area [ ]. Previous study has shown that surface roughness combined with contact angle and alkanes/ketones/fatty acids/alcohols concentration, can explain 60% of the variation in viral adsorption on organic surfaces [ ]. Hence, it seems that surface roughness can be a contributing factor to viral adsorption but the exact mechanism still needs to be fully determined, especially bearing in mind that the role of roughness on adhesion of other microorganisms is still surrounded by many controversial findings.

Porosity is one of the most relevant parameters involved in the manufacturing of membranes for the filtration processes involved in the purification of biopharmaceuticals products derived from human or animal origin. Although other methods can be used to remove virus from solutions ( e.g. , heat, radiation, solvent detergents), they can change the original state of the product or promote extensive degradation of proteins. Thus, filtration by membranes has become a popular method to reject virus particles without changing the chemical composition and characteristics through size exclusion [ , ]. The commercial virus filters were firstly designed to reject retroviruses with diameters higher than 50 nm but nanofiltration systems are effective in removing viruses with diameters between 18 and 24 nm [ ]. The membranes can be modified to add functionalities and enhance performance and durability. One strategy relies on the functionalization of polymeric membranes with polycationic chains which can damage lipid membranes of viruses [ , ]. This has been shown on polycationic glass slide coated with N,N -dodecyl methyl-polyethylenimine, which has shown potent virucidal effects killing the totality of Influenza A virus after 5 min [ ]. Likewise, polycations (polyethylenimine and generation 4.0 dendrimer) decreased the titer of bacteriophage PRD1 by at least 75% [ ].

As seen, several properties like wetting characteristics, surface features, and electrostatic interaction forces affect the interaction between materials and viruses and shall be mutually considered when designing novel materials with virucidal and antiadhesive properties.

3

Materials science to reduce viability and infectivity of viruses common to clinical settings

Transmission of viral diseases from contaminated dry surfaces is possible through self-inoculation of mucous membranes [ , ]. This is especially important for dental and hospital settings where viral particles can remain in the air and become available on surfaces potentially contributing to infection of nearby subjects [ ]. Therefore, designing novel materials with the potential to decrease virus availability, survivability, and infectivity is of utmost importance to minimize viral diseases in the public and in healthcare settings.

To prevent fomite transmission, researchers often focus on surface modifications that inhibit viral adhesion or promote protein destabilization). Designing smart materials with self-adjusting surface mechanisms could be a promising way to decrease virus availability on contaminated materials.

Surface modifications that change the docking orientation of viruses can potentially decrease their adsorption and retention onto materials. This concept has been shown with P22 virus-like particles cultured on substrates coated with different organisilanes namely 2H-Perfluorodecyltriethoxysilane (PFDS), (3-aminopropyl) triethoxysilane (APTS), and GPTS. The P22 virus-like particles present with an icosahedral structure and can be adsorbed in fivefold (S5), threefold (S3), and twofold (S2) symmetry axes. Notably, PFDS favoured adsorption by S5 symmetry, and adsorption on the other organosilanes occurred via S3 and S2 symmetries. Interestingly, APTS tends to deform the virus as it is adsorbed through the facets or the ridges (S2/S3). This orientation lower virus adsorption on APTS and GPTS by 66% and 32% relative to PFDS and can be explained by the repulsive forces acting on the hydrophobic domains of the P22 virus-like particles promoting adhesion by S3 and S2 symmetries ( Fig. 1 , [ ]).

Fine-tuning material surface charge and pH could also be promising alternatives to decrease viral availability. This has been shown with reovirus types 1 and 3, which were adsorbed by negatively charged silica when the environmental pH was lower than the virions isoelectric point [ ]. Indeed, the role of environmental pH on viral adsorption to adsorbent materials is well established. Hence, novel materials that can self-adjust the pH upon environmental changes could be promising in preventing the spread of viruses. It is possible to fabricate pH-responsive smart devices that change their wetting character by surface modification with a mixed thiol containing carboxylic groups and methyl groups [ ]. Another pH-responsive mechanism has been achieved in poly(acrylic acid) hydrogel modified with upconverting nanoparticle-assisted photocleavage of a ruthenium complex photobase. The pH of the materials has been manipulated with the use of near-infrared light in a process called photon upconversion pH manipulation where the upconverting nanoparticles change near infra-red light into blue light, triggering the release of n-butylamine from the ruthenium complex photobase, resulting in the deprotonation of the poly(acrylic acid) hydrogel [ ]. These and other strategies could be used to design re-applicable pH-responsive surface coatings. Manipulating surface charges with self-adjusting and pH-responsive materials may be interesting strategies to decrease adhesion and survivability of viruses on materials.

Alternative solution may be the development of materials with intrinsic virucidal properties. Perhaps the most explored chemical elements in this category are silver and copper, which have been deemed as an antimicrobial materials in countless publications. Silver-containing technologies, like the incorporation of silver-zeolite compounds into metals and polymers, had germicidal effects on air conducts in real healthcare settings [ ]. This effect may be related to the release of silver ions in the presence of moisture that interfere with microbial enzymatic and respiratory activities and ion binding to the genetic material [ , ]. Despite these promising findings, coating door handles with Agion silver zeolite technology have been shown to be effective against only a portion of the bacterial populations and there are concerns about the emergence of resistant strains [ ]. Notably, copper-containing surfaces present contact killing property in both moist and dry conditions [ ]. Previously, the placement of copper alloy-surfaced objects in intensive care units have reduced the rates of colonization with vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus (MRSA) and decreased the risk of healthcare-acquired infections in patients by more than half [ ]. Similarly, copper-made door handles installed in hospital presented high antibacterial activity against methicillin-resistant S. aureus even after being routinely used for 3 years [ ]. Previous work has shown Influenza A virus remained infectious on stainless steel (5 × 10 ⁵ viable virus particles at 24 h) but not on copper surfaces (5 × 10 ² viable virus particles at 6 h [ ]). The virucidal effect of copper can be further enhanced by the addition of peroxide and this combination inactivates several DNA or RNA viruses, such as phi X174, T7, phi 6, Junin, and herpes simplex viruses which have been found in contaminated medical devices [ ]. One of the potential mechanisms related to the killing by contact potential is the binding of copper to the double-helical structure of DNA promoting their disorder or the formation of crosslinks between bases on opposite DNA strands [ , ]. It is possible that such potential can also decrease virus survivability and spread in clinic and hospital settings. There is evidence that HuCoV-229E particles are severely damaged with evidence of detrimental morphological changes when genomic RNA from virus is exposed to copper surfaces [ ].

The antimicrobial potential of metal nanoparticles has been extensively reported and there are raising interests in using them for antiviral applications. For instance, silver nanoparticles have promising inhibitory potential against the formation of intracellular HepBV RNA and extracellular virions [ ]. Also, the addition of silver nanoparticles to chitosan results in a composite with antiviral activity against H1N1 Influenza A virus. The antiviral potential is dose-dependent with complete eradication of the virus at a concentration of 300 silver nanoparticles per μg of chitosan [ ]. Likewise, porous gold nanoparticles can attenuate the infectivity of Influenza A virus strains (H1N1, H3N2, and H9N2). Notably, MDCK cells had a viability of 96% when treated with viruses exposed to the gold nanoparticles whereas only 33% of the cells were viable when non-treated viruses were used [ ]. The antiviral activity of silver nanoparticles has also been confirmed against hepatitis B virus, with promising antiviral potential and low cytotoxicity with silver particles with sizes of 10 and 50 nm [ ]. Likewise, silver nanoparticles interact with HIV-1 in a size-dependent manner where only nanoparticles with sizes ranging from 1 to 10 nm have attached to virus surface [ ]. The mechanisms behind the antiviral potential of gold, silver, and copper are diverse. For instance, gold nanoparticles could interact with virus surface proteins promoting the cleavage of their disulphide bonds decreasing the infectivity potential [ ]. Silver and copper can form complexes with sulphur-containing functionalities and induce protein destabilization through the breakage of disulphide bonds [ ]. Also, silver nanoparticles bind preferentially to viral sulphur-bearing residues of gp120 glycoprotein knobs and this can prevent viral binding to host cells by blocking other proteins inhibiting post-entry stages of infection, or by binding directly to nucleic acids reducing proviral transcription processes [ , , ]. In addition, copper and silver compounds such as Ag ₂ O and CuCl ₂ can promote virus inactivation by the inhibition of neuraminidase activity whereas Cu ₂ O cause the structural denaturation of hemagglutinin, impairing host cell recognition through ligand–receptor interactions [ ].

Other strategies make use of novel materials to eradicate viruses with destruction mechanisms. Recently, a graphene derivative has been shown to inactivate both DNA and RNA viruses by structural destruction at a non-cytotoxic concentration. The antiviral mechanism was attributed to the negative charge and nanosheet structure [ ]. Likewise, graphene-like materials have inhibited HSV-1 infection through cell attachment inhibition at low concentrations [ ]. Similar potential has been observed with the Ebola virus matrix protein VP40, which has been disrupted by graphene nanosheets at the C-terminal domain interface that is crucial in forming the Ebola viral matrix [ ]. Also, graphene oxide has been shown to capture viruses and to destroy their surface proteins. Interestingly, the superficial bioreduction provided by graphene oxide allows the extraction of higher quantities of viral RNA [ ].

4

New approaches to oral antiviral delivery materials

The challenges in developing oral antiviral delivery materials are considerable, but not insurmountable. Bearing in mind the advantages of oral delivery, including easy administration, cost-effectiveness, and flexibility in dosage, it is understandable that oral drug delivery is acknowledged as one of the most preferred and convenient routes [ , ]. Frequently, this route has been used with a therapeutic focus; however, an emerging and less explored strategy is the development of sophisticated oral antiviral delivery materials to reduce the spread of viral infections transmitted orally. For instance, the oral epithelial cells have high ACE-2 expression hence it is a critical point in COVID-19 infection susceptibility [ , ]. Therefore, we envisage that health care workers and the general population, who are under high exposure risk from COVID-19 infection, are good candidates to use pre-exposure prophylaxis antivirals or inhibitors of post-entry replication via adapted antiviral-based oral drug delivery systems. The Glycyrrizin, dapivirine, and Griffithsin are powerful inhibitors of viral entry and were successfully coupled to drug delivery materials [ ]. For instance, poly(lactic- co-glycolic acid) (PLGA) nanoparticles have been design to co-deliver Griffithsin and dapivirine and this strategy has been shown to prevent viral infection in vitro [ ].

Another potential strategy to inhibit the virus infection in oral mucosa is to develop oral drug delivery materials coupled with natural occurring salivary protein/peptides with antiviral activity. Some examples of natural occurring proteins that were coupled with nanocarriers system are alpha-2-macroglobulin, mucin MUC5B, histatins 1, histatin 3 and its related peptides [ ]. Previously, chitosan-g-oligo copolymers mucoadhesive gel has been shown to deliver antiretroviral Efavirenz through mucosa in vitro [ ] Furthermore, several compounds that are capable of inhibiting post-entry replication of coronaviruses, such as broad-spectrum antiviral agent as Nitazoxanide [ ] or papain-like and chymotrypsin-like protease [ ] can be attached in microcarriers system. For instance, copolyester poly(glycol adipate-co-ω-pentadecalactone) microparticles have been shown to effectively release α-Chymotrypsin but only for 7 h [ ]. The fundamentals of these studies suggest that preventing and treating viral infections with oral delivery systems may be feasible if material properties are tailored to promote controlled and sustained release of antiviral agents in the oral cavity.

5

Optimizing antiviral delivery with artificial intelligence

A broad range of materials can be leveraged for potential innate antiviral properties, as well as the delivery of a broad spectrum of candidate therapies. This represents an opportunity to novel materials design and combination therapy ( e.g. , drug pair-based synergy prediction, to traditional target-based drug selection [ , ]). Co-delivering multiple therapies through nanoparticles emerges as a potential platform for enhanced drug synergy. However, achieving optimal drug combination design depends on the simultaneous optimization of drug and dose selection. This can be insurmountably challenging when considering the fact that a small pool of 12 drugs with each drug studied at 10 dosing levels results in 1 trillion possible drug combinations. To overcome this testing challenge, we have previously harnessed an artificial intelligence (AI)-driven quadratic relationship between drug/dose inputs and efficacy/safety outputs to markedly reduce the number of prospective assays needed to pinpoint the right drugs and doses with potential to improve treatment outcomes [ ]. To this end, the patient’s clinical/laboratorial data (baseline and follow-ups) and therapeutic regime (initial and adjusted doses) are constantly analyzed using computational power like quadratic phenotypic optimization platform. This analytical system keeps adjusting the therapeutic scheme based on new inputs till an optimal combination of drugs, dosage and administration scheme is achieved at the individual level ( Fig. 2 ). This strategy has been successfully used to customize the treatment for metastatic prostate cancer resulting in controlled PSA levels without disease progression and reduced lesion size [ ]. Likewise, AI has been used in a pilot study to optimize the dose of antiretroviral drugs for treating HIV infection. The AI platform identified that the tenofovir dose could be reduced for the long-term maintenance regimen with no relapse for 33 months [ ].

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