High‐entropy nanozymes with dual antibiofilm and pro‐regenerative functions for wound healing

Abstract The treatment of bacterial wound infection remains a significant health challenge, with the prevention of bacterial resistance and harnessing the microenvironment of lesions for biological therapy being a clinical expectation. Nanozymes, as enzyme‐mimicking catalysts, provide a promising non‐antibiotic strategy for bacterial elimination. However, their therapeutic potential has been constrained by acidic pH‐dependent catalytic activity, cytotoxicity that impedes tissue regeneration, and insufficient understanding of their bactericidal mechanisms. In this study, a high‐entropy nanozyme system was developed with antibiofilm and pro‐regenerative properties via incorporating lanthanide and zinc into a clinically approved iron‐based nanocrystal. This high‐entropy lattice modification enabled self‐adaptive catalysis via surface electron density modulation, effectively overcoming pH restrictions and enhancing peroxidase‐like activity under physiological conditions. Mechanistic investigations revealed that this optimized nanozyme could effectively cleave bacterial peptidoglycan glycosidic bonds via oxidation, disrupt membrane integrity, and induce oxidative damage to biomacromolecules through reactive oxygen species (ROS) generation, demonstrating potent antimicrobial efficacy against S. aureus , E. coli , and P. aeruginosa . Notably, these high‐entropy nanozymes exhibited good biocompatibility and promoted the migration and proliferation of fibroblasts, accelerating epithelialization and granulation tissue formation by modulating the wound microenvironment, as confirmed in both in vitro and infected wound models, with no observed adverse effects. This multi‐element doping strategy provides valuable insights into the development of novel and efficient antimicrobial materials to combat the growing threat of bacterial resistance.