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However, its clinical translation remains challenging due to the inherent limitations imposed by the bone physiological barrier. Herein, a bone cavity\u2010targeted nanocomposite (ZCD) is developed that can respond to extracorporeal shock wave (ESW), enabling triaxial regulation by inhibiting adipogenic differentiation, promoting osteogenic differentiation, and suppressing osteoclast activity. This nanocomposite is synthesized using a comprehensive drug strategy incorporating zoledronic acid, disulfiram, and calcium ions. It can specifically target bone marrow mesenchymal stem cells (BMSCs) and bone marrow monocytes (BMMs). Following ESW stimulation, the system enables controlled drug release, effectively suppressing excessive osteoclast activation and enhancing osteoblast metabolic activity at adipogenic sites in osteoporosis. This microenvironment\u2010tailored intervention successfully restores bone metabolic equilibrium, enhances bone mineral density, and improves biomechanical performance, thereby establishing a transformative paradigm for precision medicine in metabolic osteoporosis treatment.<\/jats:p>","DOI":"10.1002\/smll.202505863","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T18:08:47Z","timestamp":1757095727000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multidimensional Regulation of Bone Marrow Niche Using Extracorporeal Shock Wave Responsive Nanocomposites for Osteoporosis Therapy"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5814-0723","authenticated-orcid":false,"given":"Hao","family":"Li","sequence":"first","affiliation":[{"name":"CAS Key Laboratory for Biomedical Effects of Nanomaterial &amp; Nanosafety, Institute of High Energy Physics Chinese Academy of Sciences  Beijing 100049 China"},{"name":"The Third Medical Center of Chinese PLA General Hospital  Beijing 100039 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Hu","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory for Biomedical Effects of Nanomaterial &amp; 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