Microenvironment-Adaptive Dynamic Hydrogel with Hierarchical Therapeutic Functions for Infected Chronic Wound Healing

Infected chronic wounds are trapped in a vicious cycle of bacterial infection, oxidative stress, and inflammation. This dynamic and multifactorial pathology presents a formidable challenge that conventional dressings cannot adequately address. Herein, we report a microenvironment-adaptive dynamic hydrogel (BBR/CAT@Gel) engineered with hierarchical therapeutic functions to break this cascade. These functions consist of three integrated levels: contact killing, on-demand responsive release of antibacterial/antioxidant agents, and pro-regenerative microenvironment remodeling. To achieve these functions, the hydrogel is formed via dual dynamic covalent cross-linking through Schiff base and phenylboronate ester bonds between phenylboronic acid-grafted polylysine and chlorogenic acid-grafted oxidized hyaluronic acid, followed by encapsulation of berberine (BBR) and catalase (CAT). This reversible network endows the system with injectability, self-healing capacity, and tissue adhesion, enabling on-demand drug release in response to the acidic pH and reactive oxygen species (ROS) of the infected wound microenvironment. The hydrogel exerts multifaceted antibacterial effects through membrane disruption mediated by ε-polylysine and chlorogenic acid (CGA), as well as inhibition of bacterial protein synthesis induced by BBR. Concurrently, the released CAT and BBR provide ROS scavenging, while CGA contributes antioxidant activities, collectively alleviating oxidative stress, inhibiting macrophage M1 polarization, promoting cell migration, and facilitating angiogenesis. This hierarchical design achieves rapid bactericidal action alongside sustained microenvironment remodeling. Based on these merits, BBR/CAT@Gel rapidly cleared infection and achieved complete epidermal regeneration with well-organized collagen deposition in a mouse model of infected chronic wounds. This work establishes a rationally designed, microenvironment-adaptive hydrogel platform that integrates hierarchical therapeutic mechanisms, offering a compelling strategy for advanced chronic wound management.