Targeting viral replication complexes with mRNA-encoded nanobodies: a new frontier for antiviral design.

Emerging and re-emerging RNA viruses continue to challenge global health preparedness, underscoring the need for broad-spectrum antivirals that can be rapidly deployed. We propose a family-specific antiviral design strategy that targets conserved replication-transcription complexes (RTCs) using nanobodies delivered as mRNA therapeutics. This approach overcomes the long-standing limitation of intracellular delivery of antibody-based biologics. By expressing antiviral nanobodies directly inside infected cells via lipid-nanoparticle-encapsulated mRNA, it becomes possible to disrupt essential protein-protein interactions within viral RTCs. Using SARS-CoV-2 non-structural protein 9 (NSP9) as a proof-of-concept, we show that stabilizing non-functional NSP9 oligomers can inhibit viral replication. This combined nanobody-mRNA technology provides a versatile platform for rapid antiviral development across virus families.