Smart immunomodulatory polysaccharide hydrogels promote diabetic bone regeneration by regulating the inflammation-angiogenesis-osteogenesis axis

Diabetic bone defects (DBD) are refractory to repair because chronic inflammation, excessive reactive oxygen species (ROS), and insufficient microangiogenesis disrupt immune, vascular, and osteogenic coupling. Here, we report a smart immune polysaccharide hydrogel (HCSO@ZL) that restores this axis through controlled Zn 2+ release and microenvironmental regulation. The hydrogel is formed by coupling L-histidine-modified chitosan with oxidized konjac glucomannan to generate a pH-responsive, self-healing scaffold. Histidine-Zn 2+ coordination enables sustained Zn 2+ release for 21 days while preventing toxic burst release and, together with the nanoclay network, enhances mechanical performance, with a compressive stress of 150 kPa at 50% strain, 2.5-fold higher than HCSO. In vitro, HCSO@ZL markedly reprogrammed macrophages toward an M2 phenotype, reducing CD86 intensity by 70% relative to HCSO and promoting a metabolic shift from glycolysis to oxidative phosphorylation, accompanied by reduced lactate and succinate levels and increased arginase activity. This immunoregulatory effect translated into enhanced angiogenesis, with 3-fold greater HUVEC migration and 6-fold higher CD31 intensity than HCSO. HCSO@ZL also substantially reduced intracellular ROS and enhanced osteogenic differentiation. Mechanistically, RNA sequencing and molecular validation revealed that HCSO@ZL activates coordinated antioxidant programs through the cAMP/PKA, PI3K/AKT/NRF2, and AKT/FOXO3a axes, promoting nuclear translocation of NRF2, and FOXO3a and broad antioxidant enzyme upregulation. In a diabetic rat femoral defect model, HCSO@ZL achieved near-complete defect repair within 8 weeks, with Tb.Th and BV/TV increased by 1.86-fold and 2.73-fold, respectively, relative to the untreated defect group. This Zn 2+ -gated immunomodulatory hydrogel provides a safe and effective strategy for diabetic bone regeneration.