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In this study, a featured radial extracorporeal shock wave (rESW) responsive nano\u2010drug delivery system (NDDS) is developed for local treatment. Based on a mechanic simulation, a sequence of hollow zoledronic acid (ZOL)\u2010contained nanoparticles (HZNs) with controllable shell thickness that predicts various mechanical responsive properties is constructed by controlling the deposition time of ZOL and Ca<jats:sup>2+<\/jats:sup> on liposome templates. Attributed to the controllable shell thickness, the fragmentation of HZNs and the release of ZOL and Ca<jats:sup>2+<\/jats:sup> can be precisely controlled with the intervention of rESW. Furthermore, the distinct effect of HZNs with different shell thicknesses on bone metabolism after fragmentation is verified. In vitro co\u2010culture experiments demonstrate that although HZN2 does not have the strongest osteoclasts inhibitory effect, the best pro\u2010osteoblasts mineralization results are achieved via maintaining osteoblast\u2010osteoclast (OB\u2010OC) communication. In vivo, the HZN2 group also shows the strongest local BMD enhancement after rESW intervention and significantly improves bone\u2010related parameters and mechanical properties in the ovariectomy (OVX)\u2010induced osteoporosis (OP) rats. These findings suggest that an adjustable and precise rESW\u2010responsive NDDS can effectively improve local BMD in OP therapy.<\/jats:p>","DOI":"10.1002\/smll.202207195","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T11:16:08Z","timestamp":1679915768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A Bone\u2010Penetrating Precise Controllable Drug Release System Enables Localized Treatment of Osteoporotic Fracture Prevention via Modulating Osteoblast\u2010Osteoclast Communication"],"prefix":"10.1002","volume":"19","author":[{"given":"Haojun","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Orthopedic The Third Medical Center of Chinese People's Liberation Army General Hospital  Beijing 100039 P. R. 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