Neonatal Fc receptor (FcRn)-targeted design of protein nanocages for sustained circulation

Protein-based nanocages offer unique advantages, including highly organized and homogeneous structures, high surface-area-to-volume ratios, inherent biodegradability and biocompatibility, and broad amenability to chemical and genetic engineering. Despite significant scientific advances in nanomedicine, their short in vivo half-life remains a major obstacle to clinical translation. In this study, we report the engineering of protein nanocages with markedly enhanced pharmacokinetics through genetic fusion of neonatal Fc receptor binding domains (FBDs) to their surface. The FBD-fused protein nanocages were successfully biosynthesized, achieving high production yield and long shelf-life stability. They exhibited binding ability in a pH-dependent manner to the neonatal Fc receptor, resulting in extended in vivo half-life of up to 34-fold compared to the wild-type protein nanocages. These findings offer a viable strategy to endow protein-based nanocages with extended systemic circulation, thereby broadening their potential as next-generation therapeutic platforms.