Lithium-doped calcium silicate scaffolds induce miR-130a-rich M2 macrophage EV-accelerating diabetic bone healing through angiogenesis–osteogenic coupling and mitochondrial repair

Diabetic bone regeneration remains a formidable clinical challenge owing to persistent chronic inflammation, impaired angiogenesis, and severe cellular mitochondrial dysfunction within the hyperglycemic defect microenvironment. Although cell-free therapies using extracellular vesicles (EV) are promising for regeneration, their therapeutic efficacy is compromised by harsh physiological conditions. To overcome these multidimensional barriers, we engineered a bio-instructive lithium-doped calcium silicate (LiCS) scaffold system. This ion-releasing platform was specifically designed to reprogram the local immune responses by stimulating M2 macrophages to secrete functionally enriched EV (LiCSM2EV). In vitro investigations demonstrated that LiCSM2EV successfully dictate a prohealing immunomodulatory shift. Furthermore, under high glucose stress, these engineered EV effectively alleviated oxidative damage and restored mitochondrial bioenergetics, including ATP production and membrane potential stability, in human umbilical vein endothelial cells (HUVEC) and Wharton's jelly mesenchymal stem cells (WJMSC). Transcriptomic profiling via next-generation sequencing identified exosomal miR-130a as a pivotal therapeutic target. Mechanistically, miR-130a orchestrates robust angiogenesis–osteogenesis coupling by dually targeting distinct pathways. It promotes robust endothelial tube formation in HUVEC by suppressing GAX to activate the AKT/HIF-1α/VEGF signaling axis, while simultaneously accelerating osteogenic differentiation in WJMSC by inhibiting HDAC4 to significantly upregulate RUNX2 and its downstream extracellular matrix proteins. In vivo evaluations using a diabetic rabbit bone defect model confirmed that the synergistic LiCSM2EV system significantly promoted anti-inflammatory microenvironment remodeling, rapid neovascularization, and mature bone tissue formation. This study highlights a scaffold-based EV-mediated therapeutic paradigm that integrates ion-doped biomaterials with targeted exosomal microRNA delivery to successfully restore mitochondrial function and accelerate diabetic bone healing.