A pH-responsive hydrogel facilitates osteogenesis by coordinating immunomodulation and ROS scavenging

Diabetic bone defects suffer from impaired self-repair due to pathological microenvironments characterized by excessive reactive oxygen species (ROS) accumulation and immune dysregulation. To address this challenge, we developed a multifunctional composite hydrogel (Gel/ZR) by integrating resveratrol (RSV)-loaded ZIF-8 nanoparticles into an oxidized alginate-gelatin self-healing matrix. This system leverages the pH-responsive degradation of ZIF-8 to enable targeted release of RSV and Zn 2+ in acidic bone defect sites. Comprehensive characterization confirmed the hydrogel's injectability, self-healing properties, and sustained drug release kinetics. In vitro studies demonstrated that Gel/ZR effectively scavenged ROS, restored mitochondrial membrane potential in bone marrow mesenchymal stem cells (BMSCs), and enhanced osteogenic differentiation. It concurrently promoted pro-regenerative M2 macrophage polarization. In diabetic rat cranial defects, Gel/ZR accelerated bone regeneration, while modulating local immune responses toward tissue-reparative phenotypes. These results validate Gel/ZR as a synergistic therapeutic platform that remodels diabetic bone microenvironments through coordinated ROS elimination, immunomodulation, and osteoinduction.