Supramolecular Assembly of DNA Dendrimers and Antimicrobial Peptides for Synergistic Targeted Therapy of Infected Wounds

ABSTRACT Antimicrobial peptides (AMPs) are promising candidates to combat antibiotic resistance; however, their application is limited by low targeting efficiency and in vivo stability. Here, we present a one‐pot, template‐free method for creating a supramolecular assembly of dendritic DNA nanostructures (DDN) and AMPs, enabling effective treatment of bacterial infections and wound healing. We produce DDN through terminal deoxynucleotidyl transferase‐mediated polyadenylation extension and hierarchical self‐hybridization, without a predesigned template. The pathogen‐specific aptamer‐functionalized DDN (aDDN) can be straightforwardly prepared, shows improved serum stability, effective protection of AMPs against enzymatic degradation, and demonstrates stronger in vitro antibacterial activity than AMPs alone. Using aDDN/AMP treatment, we achieved a 99% reduction in bacteria within the wound and nearly complete wound healing in 11 days, faster than with AMP alone. Notably, significantly denser collagen regeneration was observed, with no signs of systemic toxicity. This work will help translate AMPs into effective tools to fight bacterial infections and antimicrobial resistance.