Pathology-driven catalytic nanozyme-integrated adhesive hydrogel disrupts the hyperglycemia-ROS-hypoxia loop to accelerate vascularized fracture healing in diabetes.

Abstract

Diabetes mellitus severely impair fracture healing due to a pathological microenvironment characterized by persistent hyperglycemia, excessive reactive oxygen species (ROS), tissue hypoxia, and chronic inflammation, which together suppress angiogenesis and osteogenesis. Most current biomaterial strategies target only a single pathological factor and therefore fail to disrupt the interconnected metabolic cascade that perpetuates tissue dysfunction. Here, we developed a pathology-driven catalytic nanozyme-integrated adhesive hydrogel (Gel-FQG) to simultaneously regulate hyperglycemia, oxidative stress, hypoxia, and immune imbalance in diabetic fractures. Gel-FQG incorporates glucose oxidase (GOx)-loaded Fe³⁺-quercetin nanozymes into a dynamic Schiff-base hydrogel network, providing strong tissue adhesion, injectability, and sustained catalytic activity. Through sequential glucose oxidation and H₂O₂ decomposition, Gel-FQG consumes excess glucose, scavenges ROS, and generates oxygen, thereby disrupting the hyperglycemia-ROS-hypoxia feedback loop. In vitro, Gel-FQG alleviates oxidative stress and hypoxia, promotes macrophage polarization toward the pro-regenerative M2 phenotype via suppression of the TNF-α/NF-κB/HIF-1α signaling, and enhances osteogenic and angiogenic responses under hyperglycemic conditions. In a diabetic rat femoral fracture model, local implantation of Gel-FQG significantly accelerates vascularized bone regeneration and fracture healing. These findings demonstrate that Gel-FQG actively remodels the diabetic fracture microenvironment and offers a promising strategy for diabetic bone repair.