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• Current vaccines and antivirals mainly target extracellular viral proteins prone to rapid mutation and drug resistance. • Targeting conserved non-mutagenic intracellular viral non-structural proteins (NSPs) provides an alternative strategy for efficient rational drug design. • Nanobodies targeting coronavirus NSPs and their delivery as mRNA encapsulated in lipid nanoparticles (LNPs) inhibit viral replication by stabilizing non-functional NSP forms, preventing assembly of the replication transcription complex (RTC) • This approach represents a potential broad-spectrum antiviral platform, adaptable to coronaviruses and other virus families for pandemic preparedness as well as other diseases. 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.
Blavier et al. (2025) studied this question.