Bimetallic-Gallic Acid Cross-Linked Hydrogels with Cascading Nanozyme Activity Promote Healing of MRSA-Infected Wounds by Modulating the Oxidative Stress Microenvironment

Chronic wounds caused by multidrug-resistant bacteria such as methicillin-resistant <i>Staphylococcus aureus</i> (<i>MRSA</i>) often stall during the healing process due to persistent inflammation and failed tissue repair. This pathological state primarily results from a vicious cycle formed by the interaction of oxidative stress, chronic inflammation, and impaired angiogenesis. To this end, this study employs network pharmacology to reveal that gallic acid (GA, a polyphenol with potent antioxidant and anti-inflammatory activity) promotes skin wound healing by regulating oxidative stress and apoptosis. Subsequently, based on these findings, a dynamic hydrogel dressing with cascade enzyme-like activity was developed. By synergistically modulating the oxidative stress microenvironment, eliminating bacterial infections, promoting angiogenesis, and accelerating the healing of <i>MRSA</i>-infected wounds, it effectively remodels the wound microenvironment. The core of this system is a metal-phenolic network particle (ZCG) self-assembled from Zn²⁺ (antibacterial), Cu²⁺ (angiogenic), and GA. These bioactive particles are embedded in a dynamic hydrogel matrix composed of oxidized fucoidan (OFD) and carboxymethyl chitosan (CMCS), which confer self-healing and injectable properties to the dressing. Simultaneously, by synergistically combining metal ions and GA, the hydrogel dressing functions as a "regenerative niche" that effectively eradicates <i>MRSA</i>. It further scavenges excess reactive oxygen species to alleviate inflammation and protect host cells. The system also releases pro-angiogenic copper ions to reconstruct vascular networks, effectively remodeling the wound microenvironment. This promotes collagen deposition and granulation tissue formation, accelerating wound closure. As a universal therapeutic solution for chronic nonhealing wounds, it holds significant clinical translation potential.