mRNA-delivered neutralizing antibodies confer protection against SARS-CoV-2 in animal models.

Monoclonal antibodies represent potent biological countermeasures against a wide range of human diseases; however, their clinical application and widespread use are limited by the high cost and complexity of antibody production and manufacturing. The mRNA-lipid nanoparticle (mRNA-LNP) platform offers a versatile strategy for vaccine development and protein-replacement therapies. Since the COVID-19 pandemic, a number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies have been identified, with several granted emergency use authorization for patients. Here, we report the design and generation of mRNA-LNPs encoding two SARS-CoV-2-neutralizing antibodies, 76E1 and LY1404, which, respectively, target the spike protein's fusion peptide (FP) and receptor-binding domain (RBD). We demonstrated that a single intramuscular administration of these mRNA-LNPs in mice resulted in robust antibody production that sustained in circulation for 7-14 days. Furthermore, we evaluated protective effects of these mRNA-delivered antibodies in animal models and showed that a single IM dose of mRNA-LNPs encoding LY1404 or 76E1 conferred significant protection against multiple SARS-CoV-2 variants, including Omicron BQ.1 and Delta, in mice and hamsters. Collectively, these findings highlight the potential of mRNA-based antibody delivery for rapid prevention or treatment of pathogenic infections.IMPORTANCENeutralizing antibodies represent potent biological countermeasures against viral infections. However, the high cost of antibody production restricts its clinical accessibility and large-scale application. The mRNA-lipid nanoparticle (mRNA-LNP) offers a versatile platform for developing vaccines and protein-replacement therapies. In this study, we designed and generated mRNA-LNPs encoding two SARS-CoV-2-neutralizing antibodies, 76E1 and LY1404, which target the viral spike protein's fusion peptide (FP) and receptor-binding domain (RBD), respectively. A single intramuscular administration of mRNA-LNPs encoding LY1404 or 76E1 resulted in rapid antibody production in circulation and conferred protection against multiple strains of SARS-CoV-2 infection in animal models. Our findings highlight the potential of mRNA-based antibody delivery for rapid prevention or treatment of pathogenic infections.