NIR-responsive mild photothermal hydrogels for multimodal antibacterial therapy, immunomodulation, and regenerative repair of MRSA-infected wounds

Methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds are difficult to heal because of persistent bacterial colonization, prolonged inflammatory responses, and restricted tissue regeneration. In this study, a near-infrared (NIR)-responsive photocurable hydrogel system (ZPPE@PLHA) was developed for localized anti-infective therapy and tissue repair by incorporating ZnO/PDA/PEG/rhEGF composite nanostructures into a PLMA/HAMA matrix. The results showed that this hydrogel enabled sustained Zn²⁺ release and exhibited a stable mild photothermal effect (mPTT) under 808 nm NIR irradiation, with the temperature rising to approximately 48.6 °C within 10 min. In vitro experiments demonstrated that the ZPPE@PLHA hydrogel possessed intrinsic antibacterial activity co-mediated by Zn²⁺ and ε-PL, and that NIR irradiation further enhanced its inhibitory effects against MRSA and E. coli. Phenotypic observations and bacterial transcriptomic analyses indicated that this antibacterial effect was associated with membrane damage, metabolic disruption, and suppression of translation-related processes. Meanwhile, ZPPE@PLHA attenuated macrophage inflammatory activation and promoted M2-associated polarization in both classically activated and lipoteichoic acid (LTA)-stimulated macrophages, and enhanced endothelial cell migration and tube formation. In an MRSA-infected rat wound model, treatment with ZPPE@PLHA hydrogel combined with NIR significantly reduced the MRSA burden, improved the macrophage-mediated inflammatory microenvironment, and accelerated wound closure and angiogenesis, accompanied by increased EGFR expression and enhanced phosphorylation of PI3K, AKT, and ERK. By integrating antibacterial, immunomodulatory, and pro-regenerative activities, this hydrogel provides a full-process therapeutic strategy for the management of acute infected wounds.