Broad-Spectrum Antiviral Styrene Maleic-Acid Copolymer Lipid Particle Nanodiscs for pH-Responsive Irreversible Virus Inactivation

Respiratory viruses, such as influenza A virus and SARS-CoV-2, continue to pose significant global health challenges. Current antivirals, which are often specific to a single virus, face limitations due to rapid mutations and the emergence of new strains. In this study, we introduce styrene maleic acid copolymer lipid particle nanodiscs (SMALP-NDs) as a broad-spectrum antiviral platform that employs a dual mode of action. First, SMALP-NDs bind to positively charged viral proteins via their negatively charged surfaces, thereby blocking viral entry. Second, they induce the collapse of viral envelopes under acidic conditions similar to those in the endosome, leading to virus inactivation via a cell-mediated mechanism. SMALP-NDs demonstrated broad-spectrum antiviral activity against influenza A/B and multiple SARS-CoV-2 variants, including Omicron JN.1, as well as herpes simplex virus types 1 and 2 and vaccinia virus, underscoring their versatility. Intranasal administration of SMALP-NDs has successfully protected mice from lethal H1N1 and H5N2 influenza A viruses as well as SARS-CoV-2. These findings underscore that SMALP-NDs effectively counteract the increasing positive charge of emerging viral proteins through their negatively charged surfaces while leveraging pH-responsive virus inactivation mechanisms to achieve high antiviral efficacy with low toxicity, offering a significant advantage over traditional antiviral nanomaterials.