Bone-Targeted Engineered Exosomes Delivering Betaine Alleviate Osteoporosis via Autophagy-Driven Osteogenesis

Dysregulated bone remodeling, attenuated endogenous osteogenic capacity, and the lack of bone-targeting capability in therapeutics constitute the core challenges in current clinical interventions for osteoporosis. In this study, a hybrid nanodelivery system integrating betaine-loaded metal-organic frameworks with engineered exosomes (BZ@Exos) is constructed to restore bone metabolic homeostasis and improve bone microstructure. The engineered exosomes co-overexpressing CXCR4 and CD47 proteins on the surface exhibit high bone tissue targeting efficiency and evade clearance by the mononuclear phagocyte system, while ZIF-8 enables stable encapsulation of betaine. Internalized betaine promotes nuclear translocation of TFEB via targeted binding to the 14-3-3 protein, enhances autophagic flux in senescent bone marrow mesenchymal stem cells (BMSCs), and thereby facilitates their osteogenic differentiation. In parallel, BZ@Exos significantly inhibits osteoclast-mediated bone resorption and restores bone metabolic homeostasis. In vivo assays demonstrate that intravenously administered BZ@Exos successfully reverses bone loss and alleviates senescence-related phenotypes in ovariectomized rat models of osteoporosis. This novel therapeutic system with integrated functions of bone homeostasis remodeling, regenerative potential restoration, and precise targeting provides a new perspective for osteoporosis treatment.