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The dual regulation strategy of the physical barriers of bone matrix and intracellular gene regulation generated by advanced biomaterials is a decent alternative for the treatment of PMOP. Herein, for the first time, it is identified that hsa\u2010miR\u2010378i\/mmu\u2010miR\u2010378a\u20103p are closely associated with PMOP. Then, an osteophilic and dual\u2010regulated alendronate\u2010gene lipoplex (antagomir@Aln\u2010Lipo), composed of medicative alendronate\u2010functionalized liposomal vehicle and encapsulated specific microRNAs is engineered, for bone\u2010targeting delivery of genes to achieve combined mitigation of bone loss. Alendronate targets hydroxyapatite in the bone matrix and occupies the adhesion site of osteoclasts, thus providing the \u201cphysical barriers\u201d. Antagomir is coupled precisely to specific endogenous microRNAs, thus providing the \u201cgenetic signals\u201d. These functionalized lipoplexes exhibited long\u2010term stability and good transfection efficiency. It is proven that antagomir@Aln\u2010Lipo could synergistically regulate osteoclastogenesis and bone resorption in vitro and in vivo. Furthermore, intravenous injection of antagomir@Aln\u2010Lipo efficiently reverses bone loss through a dual mechanism driven by alendronate and antagomir\u2010378a\u20103p. In conclusion, the osteophilic and dual\u2010regulated antagomir@Aln\u2010Lipo offers a brand\u2010new bifunctional strategy for the precise treatment of PMOP.<\/jats:p>","DOI":"10.1002\/smll.202303456","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T23:08:05Z","timestamp":1689203285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Osteophilic and Dual\u2010Regulated Alendronate\u2010Gene Lipoplexes for Reversing Bone Loss"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0249-9293","authenticated-orcid":false,"given":"Junjie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Second Affiliated Hospital of Soochow University Osteoporosis Research Institute of Soochow University  No.1055 Sanxiang Road Suzhou 215000 P. R. 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