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In some cases of LSDs, the bone is more severely affected, thus producing skeletal manifestations in patients. Current therapies, such as enzyme replacement therapy (ERT) and gene therapy (GT), show limited efficacy in correcting skeletal abnormalities. Increasing evidence suggests that microenvironmental disturbances also contribute significantly to disease pathogenesis. Therefore, therapeutic strategies targeting lysosomal dysfunction and microenvironmental dysregulation are needed. Mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) are emerging as promising candidates in regenerative medicine due to their immunomodulatory, pro-regenerative, and paracrine properties. MSC-EVs have shown potential to modulate the microenvironment and favor tissue repair in bone-related disorders such as osteoarthritis and osteoporosis. Interestingly, MSC-EVs can be engineered to reach the bone and carry therapeutics, including ERT- and GT-related molecules, enabling targeted delivery to hard-to-reach bone regions. This review describes the main features of MSC-EVs and discusses the therapeutic potential of MSC-EVs as a potential cell-free strategy for bone-affected LSDs.<\/jats:p>","DOI":"10.3390\/ijms26136448","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T05:54:52Z","timestamp":1751608492000},"page":"6448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mesenchymal Stem Cell-Derived Extracellular Vesicles: Seeking into Cell-Free Therapies for Bone-Affected Lysosomal Storage Disorders"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5956-1986","authenticated-orcid":false,"given":"Andr\u00e9s Felipe","family":"Leal","sequence":"first","affiliation":[{"name":"Centro de Investigaciones en Anomal\u00edas Cong\u00e9nitas y Enfermedades Raras, Universidad Icesi, Cali 760031, Colombia"},{"name":"Centro de Investigaciones Cl\u00ednicas, Fundaci\u00f3n Valle de Lili, Cali 760001, Colombia"},{"name":"Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogot\u00e1 110231, Colombia"},{"name":"Nemours Children\u2019s Health, Wilmington, DE 19803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2672-0439","authenticated-orcid":false,"given":"Harry","family":"Pachajoa","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones en Anomal\u00edas Cong\u00e9nitas y Enfermedades Raras, Universidad Icesi, Cali 760031, Colombia"},{"name":"Centro de Investigaciones Cl\u00ednicas, Fundaci\u00f3n Valle de Lili, Cali 760001, Colombia"},{"name":"Genetics Service, Fundaci\u00f3n Valle de Lili, Cali 760001, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-2160","authenticated-orcid":false,"given":"Shunji","family":"Tomatsu","sequence":"additional","affiliation":[{"name":"Nemours Children\u2019s Health, Wilmington, DE 19803, USA"},{"name":"Faculty of Arts and Sciences, University of Delaware, Newark, DE 19716, USA"},{"name":"Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1007\/s00109-020-01935-6","article-title":"Lysosomal storage diseases: Current therapies and future alternatives","volume":"98","author":"Leal","year":"2020","journal-title":"J. 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