A piezoelectrically driven hierarchical biomimetic architecture promotes diabetic bone defect repair by bidirectionally regulating HIF-1α to restore immunometabolic-vascular homeostasis

Diabetic bone defects are difficult to repair because chronic hyperglycemia disrupts local immunometabolic and vascular homeostasis, leading to persistent inflammation, poor angiogenesis, and impaired osteogenesis. Here we report a piezoelectrically driven hierarchical biomimetic architecture that promotes diabetic bone defect repair through spatially bidirectional regulation of HIF-1α. The system comprises an ultrasound-responsive PLLA/ZnO/DFO biomimetic periosteum and a conductive GelMA/MXene/Ce-MOF@Arg defect-filling hydrogel. Under ultrasound stimulation, the upper layer generates piezoelectric microcurrents and releases deferoxamine, which is associated with activation of endothelial HIF-1α/VEGF signaling and angiogenic responses, whereas the lower layer relays electrical cues into the defect core and is associated with reduced macrophage HIF-1α expression and glycolytic activity in parallel with arginine delivery and Ce-MOF nanozyme-mediated redox regulation. This design promotes recovery toward a more favorable immunometabolic-vascular state by coupling superficial pro-angiogenic activation with deep anti-inflammatory metabolic remodeling. The scaffold shows favorable piezoelectric, conductive, mechanical, degradation, and release properties, promotes endothelial migration, drives macrophage polarization toward a reparative phenotype, enhances osteogenic-angiogenic coupling, and substantially accelerates critical-sized calvarial defect healing in diabetic rats. Our findings provide an electroactive and spatially coordinated strategy for diabetic bone regeneration.