An LNP antiviral siRNA drug cocktail delivered intranasally is effective against a range of respiratory viruses.

SARS-CoV-2, influenza A virus (IAV), and respiratory syncytial virus (RSV) are leading causes of acute respiratory infections globally, often presenting with overlapping clinical features that complicate timely diagnosis and treatment. Currently, no single antiviral therapy exists that targets all three pathogens, highlighting a critical need for broad-spectrum interventions. Here, we report the development and preclinical evaluation of a multiplexed small interfering RNA (siRNA) cocktail formulated in lipid nanoparticles (LNPs) for intranasal delivery. The cocktail comprises siRNAs targeting conserved regions of the SARS-CoV-2 helicase, the RSV phosphoprotein, and the IAV polymerase acidic gene. We showed that these siRNA exhibited potent, sequence-specific antiviral activity in vitro, and their combined formulation retained efficacy across all three viruses. Importantly, intranasal administration of this multiplexed antiviral drug significantly reduced pulmonary viral loads and mitigated disease severity in murine models of SARS-CoV-2, IAV, and RSV infection. These findings demonstrate the feasibility and therapeutic potential of a multi-pathogen siRNA strategy using a single LNP delivery platform. This approach offers a flexible, broad-spectrum antiviral solution that could be deployed early in the course of respiratory illness or during outbreaks involving co-circulating respiratory viruses.