Nanomaterials have now found applications across all segments of society including but not limited to energy, environment, defense, agriculture, purification, food medicine, diagnostics, and others. The pandemic and the vulnerability of humankind to emerging viruses and other infectious diseases has renewed interest in nanoparticles as a potential new class of antivirals. In fact, a growing body of evidence in the literature suggests nanoparticles may have activity against multiple viruses including HIV, HNV, SARS-CoV-2, HBV, HCV, HSV, RSV, and others. The most described antiviral nanoparticles include copper, alloys, and oxides including zinc oxide (ZnO), titanium oxide, iron oxide, and their composites, nitrides, and other ceramic nanoparticles, as well as gold and silver nanoparticles, and sulfated and nonsulfated polysaccharides and other sulfated polymers including galactan, cellulose, polyethylenimine, chitosan/chitin, and others. Nanoparticles, synthesized via the biological or green method, also have great importance and are under major consideration these days, as their method of synthesis is easy, reliable, cost-effective, efficient, and eco-friendly, and is done using easily available sources such as bacteria, actinomycetes, yeast, fungi, algae, herbs, and plants, in comparison to chemically mediated synthesis. Chemical synthesis is highly expensive and involves toxic solvents, high pressure, energy, and high temperature conversion. Examples of biologically synthesized NPs include iron oxide, Cu and CuO NPs, and platinum and palladium NPs. In contrast to traditional medications, nanomedications have multiple advantages: their small size, increased surface to volume ratio, improved pharmacokinetics, improved biodistribution, and targeted delivery. In terms of antiviral activity, nanoscale interactions represent a unique mode of action. As reviewed here their biomedical application as an antiviral has shown four major mechanisms:(1) direct viral interaction prohibiting the virus from infecting the cell, (2) interaction to receptor or cell surface preventing the virus from entering the host cells, (3) preventing the replication of the virus, or (4) other processing mechanisms which inhibit the spread of virus. Here these pharmacologic mechanisms are reviewed and the challenges for technology translation are discussed in more detail.

Recent interest in nanomedicine has skyrocketed because of mRNA vaccine lipid nanoparticles (LNPs) against COVID-19. Ironically, despite this success, the innovative nexus between nanotechnology and biochemistry, and the impact of nanoparticles on enzyme biochemical activity is poorly understood. The studies of this group on zinc nanoparticle (ZNP) compositions suggest that nanorod morphologies are preferred and that ZNP doped with manganese or iron can increase activity against model enzymes such as luciferase, DNA polymerase, and β-galactosidase (β-Gal), with the latter previously being associated with antimicrobial activity. SARS-CoV-2 encodes several of these types of oxido-reductase, polymerase, or hydrolase types of enzymes, and while metamaterials or nanoparticle composites have become important in many fields, their application against SARS-CoV-2 has only recently been considered. Recently, this group discovered the antiviral activity of manganese-doped zinc sulfide (MnZnS), and here the interactions of this nanoparticle composite with β-Gal, angiotensin converting enzyme (ACE), and human ACE2 (hACE2), the SARS-CoV-2 receptor, are demonstrated. Low UV, circular dichroism, and zeta potential results confirm their enzyme interaction and inhibition by fluorometric area under the curve (AUC) measurements. The IC 50 of enzyme activity varied depending on the manganese percentage and surface ranging from 20 to 50 μg/mL. MnZnS NPs give a 1–2 log order inhibition of SARS-CoV-2; however, surface-capping with cysteine does not improve activity. These data suggest that Mn substituted ZNP interactions to hACE2 and potentially other enzymes may underlie its antiviral activity, opening up a new area of pharmacology ready for preclinical translation.

Conserved omicron RNA (COR) is a 40 base long 99.9% conserved sequence in SARS-CoV-2 Omicron variant, predicted to form a stable stem loop, the targeted cleavage of which can be an ideal next step in controlling the spread of variants. The Cas9 enzyme has been traditionally utilized for gene editing and DNA cleavage. Previously Cas9 has been shown to be capable of RNA editing under certain conditions. Here we investigated the ability of Cas9 to bind to single-stranded conserved omicron RNA (COR) and examined the effect of copper nanoparticles (Cu NPs) and/or polyinosinic-polycytidilic acid (poly I:C) on the RNA cleavage ability of Cas9. The interaction of the Cas9 enzyme and COR with Cu NPs was shown by dynamic light scattering (DLS) and zeta potential measurements and was confirmed by two-dimensional fluorescence difference spectroscopy (2-D FDS). The interaction with and enhanced cleavage of COR by Cas9 in the presence of Cu NPs and poly I:C was shown by agarose gel electrophoresis. These data suggest that Cas9-mediated RNA cleavage may be potentiated at the nanoscale level in the presence of nanoparticles and a secondary RNA component. Further explorations in vitro and in vivo may contribute to the development of a better cellular delivery platform for Cas9.