Smart immunomodulatory polysaccharide hydrogels promote diabetic bone regeneration by regulating the...

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 Zn²⁺ 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-Zn²⁺ coordination enables sustained Zn²⁺ 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 Zn²⁺-gated immunomodulatory hydrogel provides a safe and effective strategy for diabetic bone regeneration.