Enzyme-triggered self-assembling peptide hydrogel for localized delivery of plumbagin against MRSA-infected wounds

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major clinical challenge, particularly in wound infections where biofilm formation severely compromises antimicrobial efficacy. Here, Plumbagin (PLB), a naphthoquinone natural product, was selected as a lead anti-MRSA candidate from a high-throughput screening of 3720 natural compounds and further developed using a localized delivery strategy. PLB exhibited concentration-dependent bactericidal activity against MRSA with limited cytotoxicity toward human dermal fibroblasts. To overcome the challenges associated with poor local retention and limited sustained exposure of free PLB, PLB was incorporated into an enzyme-instructed self-assembling (EISA) peptide hydrogel. The resulting EISA-PLB hydrogel exhibited rapid gelation, favorable viscoelastic properties, and sustained PLB release under simulated wound conditions. Compared with free PLB, EISA-PLB demonstrated enhanced antibiofilm activity under physiological conditions. In a murine full-thickness MRSA-infected wound model, EISA-PLB hydrogel reduced bacterial burden and accelerated wound closure more effectively than free PLB. This study establishes an enzyme-responsive supramolecular peptide hydrogel as a localized delivery platform to improve the therapeutic application of natural antimicrobial compounds against drug-resistant wound infections.