A bifunctional molecular adaptor drives immune cell-hitchhiked delivery of protein therapeutics

Protein therapeutics hold transformative potential for disease treatment, yet their clinical efficacy remains constrained by formidable physiological and pathological barriers. Here, we present a bifunctional molecular adaptor that enables immune cell-hitchhiked transport of protein drugs. This adaptor functionalizes proteins through controllable conjugation, while simultaneously promoting their rapid entry into circulating immune cells following systemic administration. The protein-bifunctional molecule conjugates not only retain bioactivity but also exploit immune cells as endogenous carriers to achieve inflammation-targeted delivery. We delineate the structure-activity relationships governing adaptor design, revealing its high targeting efficiency and a non-endocytic internalization mechanism. In murine models of lipopolysaccharide-induced sepsis, protein-bifunctional molecule conjugates efficiently targeted inflamed organs, alleviated sepsis-induced tissue and organ damage, and improved survival in septic shock. These findings establish a bifunctional molecular adaptor as a clinically translatable strategy to overcome longstanding barriers in the targeted delivery of protein therapeutics.