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To further optimize systemic therapeutic efficacy, we functionalized m-sEV with a bone-targeting peptide:(DSS)\n                    <jats:sub>6<\/jats:sub>\n                    , thereby constructing bone-targeting engineered vesicles (Bm-sEV). Systemic administration of Bm-sEV enabled precise miR-126 targeted delivery to bone tissue, resulting in increased abundance of type H vessels in the femur, improved bone microarchitecture, and attenuation of age-related bone loss. Mechanistic analyses demonstrated that the angiogenesis-osteogenesis coupling effect was mediated by upregulation of endothelial Integrin\n                    <jats:italic>\u03b2<\/jats:italic>\n                    3 (ITGB3), which subsequently activated the ITGB3\/ERK2 signaling cascade. Notably, Bm-sEV also restored the profoundly impaired osteoclastic activity in aged femurs, thereby re-establishing skeletal homeostasis. Collectively, Our study provides a promising approach for the treatment of age-related bone loss by combining biological macromolecules such as (DSS)\n                    <jats:sub>6<\/jats:sub>\n                    and miR-126 with sEV.\n                  <\/jats:p>","DOI":"10.1088\/1748-605x\/ae7ee3","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T22:54:43Z","timestamp":1781736883000},"page":"045010","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual-engineered small extracellular vesicles targeted delivery miR-126 for reducing age-related bone loss"],"prefix":"10.1088","volume":"21","author":[{"given":"Junming","family":"Tao","sequence":"first","affiliation":[{"name":"Sichuan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiyu","family":"Du","sequence":"additional","affiliation":[{"name":"Sichuan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sichuan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengru","family":"Hong","sequence":"additional","affiliation":[{"name":"Sichuan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaochen","family":"Duan","sequence":"additional","affiliation":[{"name":"Sichuan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Datian","family":"Fu","sequence":"additional","affiliation":[{"name":"Sichuan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Chen","sequence":"additional","affiliation":[{"name":"Shenzhen Traditional Chinese Medicine Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Liang","sequence":"additional","affiliation":[{"name":"The University of Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3318-1090","authenticated-orcid":true,"given":"Wei","family":"Jing","sequence":"additional","affiliation":[{"name":"Sichuan University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"bmmae7ee3bib1","doi-asserted-by":"publisher","first-page":"2417","DOI":"10.14336\/AD.2023.1115","type":"journal-article","article-title":"Consequences of aging on bone","volume":"15","author":"Zhang","year":"2023","journal-title":"Aging Dis."},{"key":"bmmae7ee3bib2","doi-asserted-by":"publisher","first-page":"4355","DOI":"10.1002\/j.2040-4603.2023.tb00253.x","type":"journal-article","article-title":"Aging and bone metabolism","volume":"13","author":"Pignolo","year":"2023","journal-title":"Compr. 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