Lysozyme-Responsive Glycol Chitosan Hydrogel Facilitates On-Demand Release of Antibacterial Nanoparticles for Wound Healing Applications

Wound infection causes excessive inflammation, delays healing, and may lead to severe complications. An ideal dressing should release antibacterial agents on demand to eradicate pathogens locally. Enzyme-responsive drug release systems are highly biocompatible and specific, yet their application in chitosan hydrogels has been limited by imprecise control over release profiles, mechanical properties, and potential drug resistance from premature leakage. Herein, we developed a dual-enzymatically responsive chitosan hydrogel for the on-demand release of antibacterial nanoparticles (ANPs). By synthesizing a series of hydroxyphenyl- and N-acetyl-modified glycol chitosan (HPPA-GC), we tuned the hydrogel stiffness and lysozyme degradation kinetics. Broad-spectrum ANPs were encapsulated via photo-cross-linking. Lysozyme, abundant in infected wounds, triggered hydrogel degradation and ANP release in vitro. When applied to S. aureus-infected full-thickness wounds in mice, the ANP-loaded hydrogel effectively combated infection and accelerated healing. This study demonstrates a robust and biocompatible platform for enzyme-triggered antimicrobial delivery, showing promise for the future development of smart wound dressings.