Dynamic multistage nanozyme hydrogel reprograms diabetic wound microenvironment: synergistic oxidative stress alleviation and mitochondrial restoration

Chronic diabetic wounds remain a significant clinical challenge due to persistent bacterial infections, oxidative stress, impaired angiogenesis, and mitochondrial dysfunction. Traditional therapies often fail to address these interrelated pathological factors, highlighting the urgent need for innovative solutions. Here, we present a Mn-ZIF@GOx/BC (MZGB) hydrogel system, where Mn-ZIF@GOx (MZG) nanozymes are successfully integrated into a bacterial cellulose (BC) hydrogel via hydrogen bonding and electrostatic interactions. The MZGB hydrogel lowers wound pH by oxidizing excess glucose into gluconic acid. It exhibits strong ROS scavenging capabilities through its superoxide dismutase and catalase-like activities, while simultaneously providing oxygen. By restoring redox homeostasis, it protects mitochondrial function and enhances cellular energy metabolism. By reprogramming macrophages, MZGB creates a favorable immune microenvironment, significantly promoting angiogenesis through paracrine mechanisms. This facilitates cell-to-cell communication, forming a positive feedback loop. Moreover, MZGB demonstrates ROS-independent antibacterial properties. BC hydrogel ensures adhesion and moisture regulation, forming a protective barrier and maintaining an optimal wound environment. This multifunctional hydrogel represents a promising nanotherapeutic approach for efficiently treating diabetic wounds by precisely regulating the wound microenvironment.