Toxics (Jul 2024)

Evaluating Molecular Mechanism of Viral Inhibition of Aerosolized Smart Nano-Enabled Antiviral Therapeutic (SNAT) on SARS-CoV-2-Infected Hamsters

  • Anais N. Bauer,
  • John F. Williams,
  • Lok R. Pokhrel,
  • Selena Garcia,
  • Niska Majumdar,
  • Jeffrey B. Eells,
  • Paul P. Cook,
  • Shaw M. Akula

DOI
https://doi.org/10.3390/toxics12070495
Journal volume & issue
Vol. 12, no. 7
p. 495

Abstract

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Smart Nano-enabled Antiviral Therapeutic (SNAT) is a promising nanodrug that previously demonstrated efficacy in preclinical studies to alleviate SARS-CoV-2 pathology in hamsters. SNAT comprises taxoid (Tx)-decorated amino (NH2)-functionalized near-atomic size positively charged silver nanoparticles (Tx–[NH2-AgNPs]). Herein, we aimed to elucidate the molecular mechanism of the viral inhibition and safety of aerosolized SNAT treatment in SARS-CoV-2-infected golden Syrian hamsters. High-resolution transmission electron microscopy (HR-TEM) coupled with energy dispersive spectroscopy (EDS) and ELISAs showed SNAT binds directly to the SARS-CoV-2 virus by interacting with intact spike (S) protein, specifically to S2 subunit. SNAT (≥1 µg/mL) treatment significantly lowered SARS-CoV-2 infections of Calu-3 cells. Extraction-free whole transcriptome assay was used to detect changes in circulatory micronome in hamsters treated intranasally with SNAT (two doses of 10 µg/mL of 2 mL each administered 24 h apart). Uninfected hamsters treated with SNAT had altered circulatory concentrations of 18 microRNAs (8 miRNAs upregulated, 10 downregulated) on day 3 post-treatment compared to uninfected controls. SNAT-induced downregulation of miR-141-3p and miR-200b-3p may reduce viral replication and inflammation by targeting Ythdf2 and Slit2, respectively. Further, SNAT treatment significantly lowered IL-6 expression in infected hamster lungs compared to untreated infected hamsters. Taken together, we demonstrate that SNAT binds directly to SARS-CoV-2 via the S protein to prevent viral entry and propose a model by which SNAT alters the cellular miRNA-directed milieu to promote antiviral cellular processes and neutralize infection. Our results provide insights into the use of low-dose intranasally delivered SNAT in treating SARS-CoV-2 infections in a hamster model.

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