Hierarchical Glucose-Sensitive Hydrogel for Anti-IL-17 Antibody Delivery Enhances Alveolar Bone Regeneration in Diabetic Conditions

Diabetic alveolar bone regeneration is impaired by hyperglycemia-driven metabolic dysfunction and IL-17-mediated chronic inflammation, both of which suppress osteogenesis. To address immune dysregulation within the diabetic microenvironment, we engineered a glucose-responsive hierarchical hydrogel (CH/IL-17Abs@GOx/CAT) via dual-component 3D printing. This architecture spatially segregates glucose oxidase (GOx) and catalase (CAT) to enhance the efficiency of the enzymatic cascade and incorporates IL-17 antibodies (IL-17Abs) for targeted immunomodulation. The hydrogel demonstrated bone-mimetic mechanical properties and favorable biocompatibility. Compared to EDC/NHS coimmobilized controls, it exhibited superior glucose sensitivity. Under hyperglycemic inflammatory conditions, the hydrogel suppressed pro-inflammatory cytokines (TNF-α, IL-6) while elevating IL-10 levels. Rat bone marrow mesenchymal stem cells displayed higher alkaline phosphatase (ALP) activity, greater mineralization, and upregulation of osteogenic genes (<i>OPG</i>, <i>RUNX2</i>, <i>COL1A1</i>). In diabetic rats with alveolar bone defects, Western blot and qPCR confirmed reduced pro-inflammatory factors (TNF-α, IL-6) and elevated anti-inflammatory IL-10, accompanied by concurrent <i>STAT3</i> downregulation and osteogenic gene activation (<i>OPG</i>, <i>RUNX2</i>, <i>COL1A1</i>) at 2 weeks. Critically, immunofluorescence colocalization analysis provided direct spatial evidence that the hydrogel disrupted the pathogenic interaction between IL-17 and phosphorylated STAT3 within the defect microenvironment. By 8 weeks, micro-CT and histology revealed robust bone regeneration, characterized by mature collagen deposition and trabecular reconstruction. Immunohistochemistry confirmed persistent expression of osteogenic proteins (OPG, COL1A1). Major organs showed no pathological changes, confirming systemic biosafety. This glucose-responsive system integrates immunomodulation with osteogenic promotion, offering a promising strategy for diabetic bone repair by addressing the dual challenges of hyperglycemia and IL-17-mediated inflammation, thus presenting a targeted alternative to conventional growth factor-based therapies.