DEFINING THE ABILITY OF SNAT NANOTHERAPEUTIC TO INHIBIT SARS-COV-2 INFECTION AND ALTER THE HOST MICRONOME TO INDUCE AN ANTIVIRAL CELLULAR ENVIRONMENT

Abstract

MicroRNAs (miRNAs) are regulatory elements that canonically bind to target mRNAs, reducing translation and protein output. They are non-coding strands of RNA, roughly 18-25 nucleotides long, and are found in plants, animals, and some viruses. During viral infection, they can be helpful or harmful to the host, affecting the cellular environment, immunity, and viral life cycle. Understanding miRNA interactions within the host and how they impact viral infections can inform therapeutic and diagnostic innovation. Nanomedicines have broad applications in the treatment of viral infections. They are less than 100 nm, and formulations include base materials such as metals, liposomes, or polymers. The nanoparticle alone may have therapeutic properties or be a carrier for therapeutic agents. Compared to traditional antivirals, nanodrugs are designed for greater bioavailability, specificity, stability, and safety. Smart Nano-enabled Antiviral Therapeutic (SNAT) is a nanodrug that alleviated SARS-CoV-2 pathology in a preclinical study using a hamster model. It is comprised of taxoid (Tx)-decorated amino (NH2)-functionalized near-atomic size positively charged silver nanoparticles (Tx--[NH2-AgNPs]) and is delivered in aerosolized form. Herein, the molecular mechanism by which SNAT exerts antiviral effects in hamsters is determined. Results from molecular biology and virology techniques suggest SNAT binds to the S2 subunit of the viral spike (S) protein of SARS-CoV-2 to interfere with viral infectivity. Next generation sequencing (NGS) and bioinformatics data reveal SNAT-induced changes in miRNA expression with antiviral implications in vivo. In addition, infected hamsters given SNAT treatment express interleukin-6 (IL-6), a cytokine upregulated during SARS-CoV-2 infection, at the same level as uninfected controls. These findings illustrate the potential use of next-generation sequencing in the evaluation of nanotherapeutics and provide valuable insights into the antiviral molecular mechanism of SNAT. The results demonstrate the two-pronged approach by which SNAT induces antiviral effects against SARS-CoV-2; directly binding SARS-CoV-2 and neutralizing viral infection, and indirectly orchestrating a cellular environment capable of thwarting viral infection. In conclusion, our findings suggest that SNAT may serve as a novel antiviral therapeutic against SARS-CoV-2 infection.