Rejuvenated Mitochondria Restore Metabolic Plasticity to Orchestrate Angio‐Osteogenic Coupling for Osteoporotic Bone Regeneration

ABSTRACT Impaired synergistic crosstalk between angiogenesis and osteogenesis, accompanied by subsequent mitochondrial dysfunction, constitutes a critical barrier to achieving effective bone regeneration under osteoporotic conditions. However, available strategies that exploit mitochondrial dynamics as a regulatory node to guide regenerative outcomes remain largely unexplored. Here, we developed a multifunctional layered double hydroxide (LDH) based nanohybrid incorporating dexamethasone (DEX) and metformin (MET), denoted as DEX@LDH/MET, which induced a rejuvenation like mitochondrial state in bone mesenchymal stem cells (BMSCs) and reprogrammed cytoskeletal organization via septin 7 (SEPT7) GTPase activation. This coordinated regulation enabled suppression of dynamin‐related protein 1 (DRP1) mediated mitochondrial fission, thereby driving mitochondrial metabolic plasticity characterized by structural integrity, mitochondrial membrane potential, and mitochondrial homeostasis. Functionally, engineered mitochondria (eMITO), derived from BMSCs treated with DEX@LDH/MET, were transferable to vascular endothelial cells (VECs) and thus enhanced their proliferation and angiogenic activity. In an ovariectomy induced osteoporosis model, this intercellular mitochondrial transfer strategy markedly promoted vascularization and restored trabecular bone microarchitecture. Overall, this study establishes a cytoskeleton constrained mitochondrial regulatory framework for organelle engineering and intercellular mitochondrial transplantation, positioning mitochondrial rejuvenation as a targetable mechanism for organelle level regenerative therapy.