Orthogonal Fc engineering enables multiplexed delivery of mRNA-encoded bispecific antibodies that constrain viral escape.

The continuous antigenic evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has repeatedly undermined the effectiveness of monoclonal antibody (mAb) therapies, underscoring the need for innovative approaches that improve therapeutic mAb breadth and durability of protection. Here, we engineered messenger ribonucleic acid (mRNA)-encoded bispecific antibodies (bsAbs) that, upon intravenous administration in lipid nanoparticles, achieved high serum concentrations, extended half-life, and serum neutralizing titers exceeding 1:10,000 in human neonatal Fc receptor (FcRn)-expressing mice. To enhance resilience to viral escape, we used structure-guided computational design to introduce Fc modifications that promoted selective homodimerization, thereby enabling codelivery of multiple mRNA-encoded bsAbs with cognate heavy chain pairing. In vivo expression of a triple bsAb combination resulted in broad serum neutralization of historical and contemporary SARS-CoV-2 variants, including the highly mutated BA.3.2.2 lineage. Preexposure prophylaxis with the mRNA-delivered bsAb combination conferred protection against SARS-CoV-2 XBB.1.5 challenge, preventing weight loss and decreasing viral burden in the lungs compared with vehicle control treatment. Together, the results provide proof of principle for mRNA-based delivery of Fc-engineered bsAb combinations to combat SARS-CoV-2 and potentially other rapidly evolving pathogens.