Injectable self-healing hydrogel loaded with a self-assembling LL-37 derivative for treating infected skin wounds

Effective management of infected skin wounds remains a major clinical challenge, particularly as rising antibiotic resistance compromises conventional therapies. Antimicrobial peptides (AMPs) have emerged as promising alternatives, but their clinical translation is hindered by poor stability and potential toxicity. In this study, we report the rational design of a novel antimicrobial peptide, FR-20, a self-assembling derivative of the human cathelicidin LL-37, engineered for enhanced structural stability and antimicrobial efficacy. Using dynamic Schiff base cross-linking, we developed an injectable, self-healing chitosan hydrogel (CS/FR-20) loaded with FR-20. The hydrogel exhibited robust mechanical integrity, excellent injectability, and a porous microarchitecture, while maintaining strong cytocompatibility and hemocompatibility. CS/FR-20 demonstrated potent bactericidal activity against both Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). In a murine full-thickness wound infection model, it effectively eradicated bacteria, reduced inflammation, accelerated tissue regeneration, and showed no detectable systemic toxicity. These findings establish CS/FR-20 as a versatile, biocompatible platform for treating infected wounds, offering a clinically translatable strategy to overcome antibiotic resistance and promote effective wound healing.