Comb-Like Dynamic Antimicrobial Peptides for Serum-Resistant Intracellular Protein Delivery and Antibacterial Treatment

Intracellular protein delivery has increasingly attracted attention in the areas of protein drugs, vaccines, and genome editing biotherapeutics. Polymeric carriers are promising candidates for protein delivery but usually suffer from limitations such as poor serum resistance and degradability. Herein, we developed a type of comb-like dynamic antimicrobial peptide (CDAMP) to address these issues by grafting antimicrobial peptides onto a polycatechol via dynamic covalent linkages. Benefiting from their amphipathic/cationic nature and comb-like structure, CDAMPs exhibited strong protein binding capability, even in serum, and successfully delivered proteins inside cells. The dynamic linkages enabled efficient protein release triggered by pH and reactive oxygen species. More importantly, CDAMPs showed greatly improved antibacterial activity compared to free AMPs, efficiently inhibited bacterial infection in two animal models, and alleviated infection-induced inflammation by delivering superoxide dismutase. This study provides a robust strategy to design protein-delivering materials based on bioactive peptides, and the CDAMPs show promise for applications in the treatment of bacterial infections and concomitant symptoms by codelivering protein therapeutics.