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In this study, a hybrid nanodelivery system integrating betaine\u2010loaded metal\u2010organic frameworks with engineered exosomes (BZ@Exos) is constructed to restore bone metabolic homeostasis and improve bone microstructure. The engineered exosomes co\u2010overexpressing CXCR4 and CD47 proteins on the surface exhibit high bone tissue targeting efficiency and evade clearance by the mononuclear phagocyte system, while ZIF\u20108 enables stable encapsulation of betaine. Internalized betaine promotes nuclear translocation of TFEB via targeted binding to the 14\u20103\u20103 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\u2010mediated bone resorption and restores bone metabolic homeostasis. In vivo assays demonstrate that intravenously administered BZ@Exos successfully reverses bone loss and alleviates senescence\u2010related 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.<\/jats:p>","DOI":"10.1002\/adma.75185","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T07:24:25Z","timestamp":1790493865000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bone\u2010Targeted Engineered Exosomes Delivering Betaine Alleviate Osteoporosis via Autophagy\u2010Driven Osteogenesis"],"prefix":"10.1002","author":[{"given":"Xiaorong","family":"Li","sequence":"first","affiliation":[{"name":"Digestive Diseases Center Guangdong Provincial Key Laboratory of Digestive Cancer Research The Seventh Affiliated Hospital of Sun Yat\u2010sen University  Shenzhen Guangdong 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