Engineering nasally delivered IgM antibodies for respiratory viral infections

Respiratory viral infections remain a significant global health burden, requiring interventions that establish robust defense directly at the portal of entry. Intranasal delivery of engineered IgM antibodies represents a highly potent platform for achieving mucosal protection. In this review, we evaluate the structural and functional rationale for prioritizing engineered IgM antibodies for mucosal immunity, provide preclinical evidence of their efficacy against respiratory viruses, and critically analyze the biomanufacturing and formulation strategies necessary for clinical translation. While bivalent antibodies are highly susceptible to viral mutational escape, the avidity-driven affinity enhancement provided by IgM scaffolds enables superior cross-linking of virions. This effectively immobilizes antigenically drifted variants and facilitates rapid mucociliary clearance, demonstrating superior efficacy against respiratory pathogens compared to their parental IgG isotypes. Concurrently, emerging biomanufacturing, purification, and formulation strategies are successfully overcoming historical stability and production hurdles to enable clinical translation. By addressing these translational challenges, this review provides a comprehensive roadmap for developing engineered IgM into a robust, variant-agnostic mucosal defense strategy against emerging and reemerging respiratory threats.