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.