Tiantian Wu, Zhengquan Xu, Guohui Yi, D. Y. Wang, Shun Chen, Shun Zhang, Bingting Xin, Tianyu Yao, Wenqin Su, Qianxi Chen, Kelong Fan, Yang Zhu
ABSTRACT The complex microenvironment of infectious chronic wounds (CWME) significantly impairs healing efficacy, necessitating dynamic, stage‐specific therapeutic modulation. Here, we report a CWME‐responsive metal–polyphenol‐coordinated nanozyme, termed F@Gala, synthesized via Fe 3+ chelation with the bioactive flavonoid galangin. Under near‐infrared irradiation, F@Gala efficiently catalyzes the conversion of endogenous hydrogen peroxide into bactericidal hydroxyl radicals in the acidic CWME during early infection. As the infection resolves and the wound environment normalizes, F@Gala transitions to catalase‐ and superoxide dismutase‐like antioxidant activities, mitigating oxidative damage and suppressing inflammation. Simultaneously, released galangin modulates macrophage polarization from pro‐inflammatory M1 to reparative M2 phenotypes, promoting angiogenesis, collagen deposition, and tissue regeneration. In vitro assays and transcriptomic analysis confirm that macrophage regulation is pivotal across all wound‐healing stages. In a diabetic wound model, F@Gala combined with photothermal therapy enables robust antibacterial activity, immune modulation, and tissue repair across the infection, inflammation, proliferation, and remodeling phases. This work presents a versatile and clinically translatable nanozyme platform for all‐stage infectious chronic wound management, offering a promising paradigm for microenvironment‐targeted therapeutic strategies.