MiR-451a-Enriched Small Extracellular Vesicles Derived from Mg²⁺-Activated DPSCs Induce Vascularized Bone Regeneration through the AKT/eNOS/NO Axis

Blood vessel formation is a necessary part of bone tissue regeneration. MSCs-sEVs play a vital role in the in vivo bone regeneration strategy. However, natural MSCs-sEVs suffer from limited blood vessel formation potency, which makes it difficult to induce vascularized bone regeneration. Here, sEVs derived from magnesium cation-activated DPSCs (Mg²⁺-EVs) are purified and found to have superior potential in promoting endothelial cell migration and angiogenesis, as well as BMSC proliferation and osteogenesis. The beneficial effects of Mg²⁺-EVs could be attributed to the enrichment of miR-451a and the subsequent regulation and activation of AKT/eNOS signaling pathways. On this basis, Mg²⁺-EVs are delivered on β-TCP-modified GelMA scaffolds for slow release and better bioavailability. The rat cranial defect model verifies that GelMA/β-TCP with Mg²⁺-EVs has enhanced potential of inducing vascularized bone regeneration. The present study provides a cation-activated strategy to modulate the cargos and contents of MSC-derived sEVs, obtaining desirable vascular promotion and bone regeneration potential. Furthermore, the developed β-TCP-modified delivery scaffolds represent a promising strategy for efficient loading and slow-release delivery of sEVs for clinical translation.