A pH-Responsive Polysaccharide Hydrogel Modulates Oxygen Delivery and Immunometabolic Remodeling for Diabetic Bone Regeneration

Diabetic bone defects are difficult to repair because chronic hypoxia, oxidative stress, persistent inflammation, and impaired osteoangiogenic coupling disrupt the healing cascade. Here, we report a pH-responsive polysaccharide hydrogel, GOZ6, for spatiotemporally coordinated diabetic bone regeneration. GOZ6 is formed by dynamic Schiff base crosslinking between gelatin and oxidized konjac glucomannan and co-delivers ZIF-8@CaO2 and 6-gingerol, integrating gated oxygen release, calcium ion delivery, antioxidative protection, and immunomodulation. The hydrogel exhibited rapid gelation within approximately 67 s, a porous architecture with a porosity of 75.78%, pH-responsive degradation, and sustained oxygen release for up to 14 d under physiological conditions. Under mildly acidic conditions, approximately 60% of 6-gingerol was released within the first 3 d, supporting early anti-inflammatory and antioxidative intervention. In vitro, GOZ6 maintained cell viability above 90%, promoted macrophage polarization toward a reparative phenotype, suppressed pro-inflammatory cytokine production, and restored oxidative metabolism. Transcriptomic and protein analyses find that JAK1-STAT3 and PI3K-AKT may serve as central pathways involved in these effects. Moreover, the GOZ6-conditioned immune microenvironment enhanced endothelial migration and tube formation, alleviated oxidative stress in bone marrow mesenchymal stem cells, restored mitochondrial function, and promoted osteogenic differentiation. In a diabetic rat calvarial defect model, GOZ6 markedly enhanced vascularized bone regeneration, collagen deposition, and osteogenic marker expression while reducing local inflammation, without evident systemic toxicity. GOZ6 therefore provides a multifunctional strategy for converting diabetic bone defects into a repair-permissive microenvironment.