{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:24:13Z","timestamp":1790666653693,"version":"4.1.0"},"reference-count":100,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Extracellular vesicles (EVs) have emerged as fundamental pillars of intercellular communication, acting as primary mediators of the bidirectional biochemical crosstalk within the integrated bone\u2013muscle unit. This review provides a comprehensive synthesis of EV-mediated signaling across the bone\u2013muscle axis, offering a side-by-side mapping of vesicular biogenesis, cargo composition, and functional roles in both tissues. Under physiological conditions, skeletal muscle- and bone-derived EVs orchestrate tissue homeostasis, adaptations to physical exercise, myogenesis, and bone remodeling by transferring unique molecular cargos of proteins and specific microRNAs. However, aging induces a profound remodeling of the EV secretome toward a senescent profile characterized by harmful vesicular factors. This dysfunctional vesicular signaling impairs both muscle regeneration and osteogenesis, directly contributing to the pathogenesis of interconnected age-related disorders like sarcopenia, osteoporosis, and osteosarcopenia. Concurrently, circulating EVs represent valuable, minimally invasive biomarkers for early diagnosis. On the therapeutic front, this review critically evaluates emerging EV-based approaches, utilizing mesenchymal stem cell-derived, bioengineered, or biomaterial-incorporated EVs, offering promising, low-immunogenic alternatives to cell transplantation to enhance musculoskeletal tissue repair and restore bone\u2013muscle homeostasis. Despite persisting technical challenges regarding large-scale production and standardization, targeting or leveraging EV-mediated communication represents one of the most innovative and revolutionary strategies to counteract age-related musculoskeletal decline. By unifying physiological mechanisms, age-related molecular reprogramming, and therapeutic engineering across both muscle and bone into a single narrative, this review provides a comprehensive framework to guide future research and clinical translation in musculoskeletal health.<\/jats:p>","DOI":"10.3390\/cells15151413","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:42:36Z","timestamp":1785850956000},"page":"1413","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Vesicular Communication in the Bone\u2013Muscle Unit: Physiological Functions, Aging, and Therapeutic Potential"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4543-7770","authenticated-orcid":false,"given":"Virginia Veronica","family":"Visconti","sequence":"first","affiliation":[{"name":"Department of Biomedicine and Prevention, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3205-4030","authenticated-orcid":false,"given":"Chiara","family":"Greggi","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, \u201cPoliclinico Tor Vergata\u201d Foundation, Viale Oxford 81, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5897-5560","authenticated-orcid":false,"given":"Antonio","family":"Matticari","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, \u201cPoliclinico Tor Vergata\u201d Foundation, Viale Oxford 81, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1826-2880","authenticated-orcid":false,"given":"Riccardo","family":"Iundusi","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, \u201cPoliclinico Tor Vergata\u201d Foundation, Viale Oxford 81, 00133 Rome, Italy"},{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Gasbarra","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, \u201cPoliclinico Tor Vergata\u201d Foundation, Viale Oxford 81, 00133 Rome, Italy"},{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4031-5624","authenticated-orcid":false,"given":"Annalisa","family":"Botta","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0330-2189","authenticated-orcid":false,"given":"Umberto","family":"Tarantino","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, \u201cPoliclinico Tor Vergata\u201d Foundation, Viale Oxford 81, 00133 Rome, Italy"},{"name":"Faculty of Medicine and Surgery, University \u201cOur Lady of Good Counsel\u201d, Rruga Dritan Hoxha, 1000 Tirana, Albania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Witwer","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0022-5320(67)80034-0","article-title":"Fine structure of early cartilage calcification","volume":"20","author":"Bonucci","year":"1967","journal-title":"J. Ultrastruct. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1083\/jcb.35.1.81","article-title":"Electron microscopic studies of induced cartilage development and calcification","volume":"35","author":"Anderson","year":"1967","journal-title":"J. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.cmet.2017.12.001","article-title":"Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise","volume":"27","author":"Whitham","year":"2018","journal-title":"Cell Metab."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Jia, J., Wang, L., Zhou, Y., Zhang, P., and Chen, X. (2025). Muscle-derived extracellular vesicles mediate crosstalk between skeletal muscle and other organs. Front. Physiol., 15.","DOI":"10.3389\/fphys.2024.1501957"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Wang, X., Huang, H., Chen, J., Zhang, Q., Yuan, Z., Yin, M., Peng, C., and Liu, S. (2026). Mechanism of exercise-derived circulating exosomes as a target for sarcopenia management. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1680485"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrendo.2012.49","article-title":"Muscles, exercise and obesity: Skeletal muscle as a secretory organ","volume":"8","author":"Pedersen","year":"2012","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41574-022-00641-2","article-title":"Exerkines in health, resilience and disease","volume":"18","author":"Chow","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rome, S. (2022). Muscle and Adipose Tissue Communicate with Extracellular Vesicles. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137052"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Trovato, E., Di Felice, V., and Barone, R. (2019). Extracellular Vesicles: Delivery Vehicles of Myokines. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00522"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Forterre, A., Jalabert, A., Berger, E., Baudet, M., Chikh, K., Errazuriz, E., De Larichaudy, J., Chanon, S., Weiss-Gayet, M., and Hesse, A.-M. (2014). Proteomic Analysis of C2C12 Myoblast and Myotube Exosome-Like Vesicles: A New Paradigm for Myoblast-Myotube Cross Talk?. PLoS ONE, 9.","DOI":"10.1371\/annotation\/ecd1e074-2618-4ad0-95c0-efdb467c714b"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1016\/j.yexcr.2010.04.006","article-title":"C2C12 myoblasts release micro-vesicles containing mtDNA and proteins involved in signal transduction","volume":"316","author":"Guescini","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rome, S., Forterre, A., Mizgier, M.L., and Bouzakri, K. (2019). Skeletal Muscle-Released Extracellular Vesicles: State of the Art. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00929"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1113\/JP278929","article-title":"The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise","volume":"599","author":"Vechetti","year":"2020","journal-title":"J. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28239","DOI":"10.3402\/jev.v4.28239","article-title":"Physical exercise induces rapid release of small extracellular vesicles into the circulation","volume":"4","author":"Helmig","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zheng, Y., Streleckis, A.C., Chen, H., and Yao, Y. (2025). Enzymatic Isolation of Skeletal Muscle Interstitial Extracellular Vesicles. J. Vis. Exp., e67439.","DOI":"10.3791\/67439"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"pgac173","DOI":"10.1093\/pnasnexus\/pgac173","article-title":"Skeletal Muscle Releases Extracellular Vesicles with Distinct Protein and MicroRNA Signatures That Function in the Muscle Microenvironment","volume":"1","author":"Watanabe","year":"2022","journal-title":"PNAS Nexus"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"151372","DOI":"10.1016\/j.ejcb.2023.151372","article-title":"Extracellular vesicles on the move: Traversing the complex matrix of tissues","volume":"102","author":"Arif","year":"2023","journal-title":"Eur. J. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"C859","DOI":"10.1152\/ajpcell.00057.2021","article-title":"Emerging role of MyomiRs as biomarkers and therapeutic targets in skeletal muscle diseases","volume":"321","author":"Srivastava","year":"2021","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1016\/j.bbalip.2016.02.010","article-title":"miRNA regulation of white and brown adipose tissue differentiation and function","volume":"1861","author":"Price","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/s42255-024-01214-5","article-title":"Metabolic Messengers: Small extracellular vesicles","volume":"7","author":"Rohm","year":"2025","journal-title":"Nat. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Chidester, S., Livinski, A.A., Fish, A.F., and Joseph, P.V. (2020). The Role of Extracellular Vesicles in \u03b2-Cell Function and Viability: A Scoping Review. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00375"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrcardio.2017.7","article-title":"Extracellular vesicles in coronary artery disease","volume":"14","author":"Boulanger","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1096\/fba.2021-00035","article-title":"Extracellular Vesicles in neural cell interaction and CNS homeostasis","volume":"3","author":"Schnatz","year":"2021","journal-title":"FASEB BioAdvances"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nri3622","article-title":"Regulation of immune responses by extracellular vesicles","volume":"14","author":"Robbins","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Porcu, C., Dobrowolny, G., and Scicchitano, B.M. (2024). Exploring the Role of Extracellular Vesicles in Skeletal Muscle Regeneration. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115811"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.stem.2016.09.010","article-title":"Myogenic Progenitor Cells Control Extracellular Matrix Production by Fibroblasts during Skeletal Muscle Hypertrophy","volume":"20","author":"Fry","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.18632\/aging.101874","article-title":"Muscle-derived miR-34a increases with age in circulating extracellular vesicles and induces senescence of bone marrow stem cells","volume":"11","author":"Fulzele","year":"2019","journal-title":"Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e15362","DOI":"10.1002\/advs.202515362","article-title":"Atrophic Skeletal Muscle-Derived Extracellular Vesicles Transfer miR-125a-5p to Inhibit Bone Formation in Osteoporosis during Aging","volume":"13","author":"Shao","year":"2026","journal-title":"Adv. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1007\/s11914-019-00537-7","article-title":"Exosomes and Extracellular RNA in Muscle and Bone Aging and Crosstalk","volume":"17","author":"Qin","year":"2019","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e70205","DOI":"10.1002\/jev2.70205","article-title":"The Role of Extracellular Vesicles in Musculoskeletal Diseases","volume":"14","author":"Fu","year":"2025","journal-title":"J. Extracell. Vesicles"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12157","DOI":"10.1073\/pnas.1516622112","article-title":"The myokine irisin increases cortical bone mass","volume":"112","author":"Colaianni","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/ijos.2015.22","article-title":"The role of microRNAs in bone remodeling","volume":"7","author":"Jing","year":"2015","journal-title":"Int. J. Oral Sci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Singh, M., Singh, P., Singh, B., Sharma, K., Kumar, N., Singh, D., and Mastana, S. (2024). Molecular Signaling Pathways and MicroRNAs in Bone Remodeling: A Narrative Review. Diseases, 12.","DOI":"10.3390\/diseases12100252"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Yuze, M., Hu, J., Jun, L., Cheng, X., Tianwen, X., and Junqiang, Z. (2025). Osteocytes function as biomechanical signaling hubs bridging mechanical stress sensing and systemic adaptation. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1629273"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10872","DOI":"10.1038\/ncomms10872","article-title":"Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation","volume":"7","author":"Li","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1186\/s12967-025-07379-1","article-title":"Exosomes in aging and age-related disorders: Mechanisms, therapeutic potentials, and challenges","volume":"23","author":"Safaei","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41413-023-00313-5","article-title":"The role and applications of extracellular vesicles in osteoporosis","volume":"12","author":"Fang","year":"2024","journal-title":"Bone Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1172\/JCI77716","article-title":"MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation","volume":"125","author":"Li","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Subramaniam, R., Vijakumaran, U., Shanmuganantha, L., Law, J.-X., Alias, E., and Ng, M.-H. (2023). The Role and Mechanism of MicroRNA 21 in Osteogenesis: An Update. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411330"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Proia, P., Rossi, C., Alioto, A., Amato, A., Polizzotto, C., Pagliaro, A., Kuli\u015b, S., and Baldassano, S. (2023). MiRNAs Expression Modulates Osteogenesis in Response to Exercise and Nutrition. Genes, 14.","DOI":"10.20944\/preprints202308.0220.v1"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9269","DOI":"10.3390\/cimb46090548","article-title":"The Role of Extracellular Vesicles in Bone Regeneration and Associated Bone Diseases","volume":"46","author":"Wan","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_44","first-page":"18","article-title":"RANKL and RANK in extracellular vesicles: Surprising new players in bone remodeling","volume":"2","author":"Holliday","year":"2021","journal-title":"Extracell. Vesicles Circ. Nucleic Acids"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41421-025-00853-6","article-title":"Cell signaling and transcriptional regulation of osteoclast lineage commitment, differentiation, bone resorption and diseases","volume":"12","author":"Zhu","year":"2026","journal-title":"Cell Discov."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ansari, S., de Wildt, B.W.M., Vis, M.A.M., de Korte, C.E., Ito, K., Hofmann, S., and Yuana, Y. (2021). Matrix Vesicles: Role in Bone Mineralization and Potential Use as Therapeutics. Pharmaceuticals, 14.","DOI":"10.3390\/ph14040289"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e13323","DOI":"10.1111\/cpr.13323","article-title":"Senescent cells: A therapeutic target for osteoporosis","volume":"55","author":"Wang","year":"2022","journal-title":"Cell Prolif."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"116540","DOI":"10.1016\/j.bone.2022.116540","article-title":"Cytokine-mediated immunomodulation of osteoclastogenesis","volume":"164","author":"Zhou","year":"2022","journal-title":"Bone"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lombardo, M., Aiello, G., Fratantonio, D., Karav, S., and Baldelli, S. (2024). Functional Role of Extracellular Vesicles in Skeletal Muscle Physiology and Sarcopenia: The Importance of Physical Exercise and Nutrition. Nutrients, 16.","DOI":"10.3390\/nu16183097"},{"key":"ref_50","first-page":"e50863","article-title":"HDAC inhibitors tune miRNAs in extracellular vesicles of dystrophic muscle-resident mesenchymal cells","volume":"21","author":"Consalvi","year":"2020","journal-title":"Embo Rep."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Oliveira, G.P., Porto, W.F., Palu, C.C., Pereira, L.M., Petriz, B., Almeida, J.A., Viana, J., Filho, N.N.A., Franco, O.L., and Pereira, R.W. (2018). Effects of Acute Aerobic Exercise on Rats Serum Extracellular Vesicles Diameter, Concentration and Small RNAs Content. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.00532"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e10686","DOI":"10.1002\/jbm4.10686","article-title":"Extracellular Vesicles as Communicators of Senescence in Musculoskeletal Aging","volume":"6","author":"Alfonzo","year":"2022","journal-title":"JBMR Plus"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s00391-022-02150-3","article-title":"Welche Rolle spielen extrazellul\u00e4re Vesikel bei der Entwicklung von Frailty und Sarkopenie?","volume":"56","author":"Wang","year":"2022","journal-title":"Z. Gerontol. Geriatr."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12951-025-03906-w","article-title":"Advances in extracellular vesicle-based nanomedicine for regenerative orthopaedics","volume":"24","author":"Pilar","year":"2025","journal-title":"J. Nanobiotechnology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4088","DOI":"10.7150\/ijbs.69816","article-title":"Extracellular Vesicles in Bone Homeostasis: Emerging Mediators of Osteoimmune Interactions and Promising Therapeutic Targets","volume":"18","author":"Huang","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Biswas, S., Gangadaran, P., Dhara, C., Ghosh, S., Phadikar, S.D., Chakraborty, A., Mahajan, A.A., Mondal, R., Chattopadhyay, D., and Banerjee, T. (2025). Extracellular Vesicles in Osteogenesis: A Comprehensive Review of Mechanisms and Therapeutic Potential for Bone Regeneration. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47080675"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Goto, K., Watanabe, D., Yanagida, K., Takagi, T., and Mizushima, A. (2025). Harnessing miRNA-Containing Extracellular Vesicles from Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Regeneration of Bone Defects: A Narrative Review of Mechanisms, Biomaterials, and Clinical Translation. Cancers, 17.","DOI":"10.3390\/cancers17152438"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Yuan, F.-L., Wu, Q.-Y., Miao, Z.-N., Xu, M.-H., Xu, R.-S., Jiang, D.-L., Ye, J.-X., Chen, F.-H., Zhao, M.-D., and Wang, H.-J. (2018). Osteoclast-Derived Extracellular Vesicles: Novel Regulators of Osteoclastogenesis and Osteoclast\u2013Osteoblasts Communication in Bone Remodeling. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.00628"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13287-024-03639-x","article-title":"Osteogenic human MSC-derived extracellular vesicles regulate MSC activity and osteogenic differentiation and promote bone regeneration in a rat calvarial defect model","volume":"15","author":"Shanbhag","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Carbonare, L.D., Minoia, A., Braggio, M., Piritore, F.C., Vareschi, A., Cominacini, M., Gandini, A., Antoniazzi, F., Cui, D., and Romanelli, M.G. (2025). Extracellular Vesicles in Osteogenesis: Comparative Analysis of Stem Cell Sources, Conditioning Strategies, and In Vitro Models Toward Advanced Bone Regeneration. Cells, 15.","DOI":"10.3390\/cells15010027"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41413-018-0007-x","article-title":"Mechanically induced Ca2+ oscillations in osteocytes release extracellular vesicles and enhance bone formation","volume":"6","author":"Morrell","year":"2018","journal-title":"Bone Res."},{"key":"ref_62","first-page":"192","article-title":"M2 exosomes modified by hydrogen sulfide promoted bone regeneration by moesin mediated endocytosis","volume":"31","author":"Zhou","year":"2024","journal-title":"Bioact. Mater."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kim, J.-M., Lin, C., Stavre, Z., Greenblatt, M.B., and Shim, J.-H. (2020). Osteoblast-Osteoclast Communication and Bone Homeostasis. Cells, 9.","DOI":"10.3390\/cells9092073"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.2147\/IJN.S441467","article-title":"Mesenchymal Stem Cell-Derived Extracellular Vesicles in Bone-Related Diseases: Intercellular Communication Messengers and Therapeutic Engineering Protagonists","volume":"19","author":"Wang","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/brv.12353","article-title":"Coupling factors and exosomal packaging microRNAs involved in the regulation of bone remodelling","volume":"93","author":"Zhu","year":"2017","journal-title":"Biol. Rev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.bone.2015.05.022","article-title":"Osteoblast-derived microvesicles: A novel mechanism for communication between osteoblasts and osteoclasts","volume":"79","author":"Deng","year":"2015","journal-title":"Bone"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Mazziotta, C., Lanzillotti, C., Iaquinta, M.R., Taraballi, F., Torreggiani, E., Rotondo, J.C., Ot\u00f2n-Gonzalez, L., Mazzoni, E., Frontini, F., and Bononi, I. (2021). MicroRNAs Modulate Signaling Pathways in Osteogenic Differentiation of Mesenchymal Stem Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052362"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"136","DOI":"10.4252\/wjsc.v5.i4.136","article-title":"Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts","volume":"5","author":"Fakhry","year":"2013","journal-title":"World J. Stem Cells"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1016\/j.bbagen.2009.09.006","article-title":"Role of matrix vesicles in biomineralization","volume":"1790","author":"Golub","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA) -Gen. Subj."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Sheng, M.H.-C., Rundle, C.H., and Lau, K.-H.W. (2025). Microvesicles Released by Osteoclastic Cells Exhibited Chondrogenic, Osteogenic, and Anti-Inflammatory Activities: An Evaluation of the Feasibility of Their Use for Treatment of Osteoarthritis in a Mouse Model. Cells, 14.","DOI":"10.3390\/cells14030193"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"687","DOI":"10.20517\/evcna.2025.58","article-title":"Extracellular vesicles in bone aging: Therapeutic strategies and applications","volume":"6","author":"Tang","year":"2025","journal-title":"Extracell. Vesicles Circ. Nucleic Acids"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"589123","DOI":"10.2147\/IJN.S589123","article-title":"The Dual Role of Extracellular Vesicles in Aging and Age-Related Diseases: Pathophysiology and Therapeutic Potential","volume":"21","author":"Zhu","year":"2026","journal-title":"Int. J. Nanomed."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/s13287-025-04374-7","article-title":"Extracellular vesicles in age-related diseases: Disease pathogenesis, intervention, and biomarker","volume":"16","author":"Putri","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Ingangi, V., Amoroso, D., Passaro, E., Di Vaia, V., Maltoni, F., Narimanfar, G., Minopoli, M., Rosa, R., Ametrano, M., and Di Gennaro, E. (2026). Understanding hairy cell leukemia in the context of mature B\u2212cell neoplasms: Tumor microenvironment and extracellular vesicle contribution to disease pathogenesis. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1741794"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Yao, H., Cui, Y., Li, P., Sun, S., Peng, C., and Wu, D. (2026). The role and mechanisms of bone microenvironment regulators in osteoporosis: Novel intervention strategies for addressing the challenges of aging. Front. Endocrinol., 17.","DOI":"10.3389\/fendo.2026.1783422"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1055\/a-1015-0285","article-title":"MiR-214 Attenuates the Osteogenic Effects of Mechanical Loading on Osteoblasts","volume":"40","author":"Yuan","year":"2019","journal-title":"Int. J. Sports Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"16015","DOI":"10.1038\/celldisc.2016.15","article-title":"Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity","volume":"2","author":"Sun","year":"2016","journal-title":"Cell Discov."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"11240","DOI":"10.1074\/jbc.RA119.007625","article-title":"Mature osteoclast\u2013derived apoptotic bodies promote osteogenic differentiation via RANKL-mediated reverse signaling","volume":"294","author":"Ma","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1038\/s41467-022-28673-2","article-title":"Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo","volume":"13","author":"Uenaka","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Luo, J., Li, L., Shi, W., Xu, K., Shen, Y., and Dai, B. (2025). Oxidative stress and inflammation: Roles in osteoporosis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1611932"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Stojanovic, B., Jovanovic, I., Stojanovic, M.D., Stojanovic, B.S., Kovacevic, V., Radosavljevic, I., Jovanovic, D., Kovacevic, M.M., Zornic, N., and Arsic, A.A. (2025). Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons. Antioxidants, 14.","DOI":"10.3390\/antiox14080987"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4459","DOI":"10.7150\/thno.72676","article-title":"Influences of age, race, and sex on extracellular vesicle characteristics","volume":"12","author":"Hooten","year":"2022","journal-title":"Theranostics"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1759720X221138354","DOI":"10.1177\/1759720X221138354","article-title":"Sarcopenia and bone health: New acquisitions for a firm liaison","volume":"14","author":"Tarantino","year":"2022","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s40520-021-01968-y","article-title":"Osteosarcopenia, the co-existence of osteoporosis and sarcopenia, is associated with social frailty in older adults","volume":"34","author":"Inoue","year":"2021","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"113751","DOI":"10.1016\/j.jconrel.2025.113751","article-title":"Bioengineered bacterial extracellular vesicles for targeted delivery of an osteoclastogenesis-inhibitory peptide to alleviate osteoporosis","volume":"382","author":"Kong","year":"2025","journal-title":"J. Control. Release"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1016\/j.apsb.2026.01.007","article-title":"Bacterial extracellular vesicles as bioactive nanocarriers for wound treatment","volume":"16","author":"Shi","year":"2026","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2004831","DOI":"10.1002\/advs.202004831","article-title":"Extracellular Vesicles from Child Gut Microbiota Enter into Bone to Preserve Bone Mass and Strength","volume":"8","author":"Liu","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.bone.2015.02.010","article-title":"Bone and muscle: Interactions beyond mechanical","volume":"80","author":"Brotto","year":"2015","journal-title":"Bone"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1186\/s12967-025-07315-3","article-title":"Roles of skeletal muscle-derived exosomes in osteoporosis","volume":"23","author":"He","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"156333","DOI":"10.1016\/j.metabol.2025.156333","article-title":"Exosomal miRNAs in muscle-bone crosstalk: Mechanistic links, exercise modulation and implications for sarcopenia, osteoporosis and osteosarcopenia","volume":"170","author":"Zhang","year":"2025","journal-title":"Metabolism"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/agm2.70078","article-title":"The Role of Extracellular Vesicles MicroRNAs in Sarcopenia: From Aging to Multi-Morbidity","volume":"9","author":"Huang","year":"2026","journal-title":"Aging Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e12163","DOI":"10.1002\/jev2.12163","article-title":"Active cargo loading into extracellular vesicles: Highlights the heterogeneous encapsulation behaviour","volume":"10","author":"Chen","year":"2021","journal-title":"J. Extracell. Vesicles"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1186\/s13287-021-02303-y","article-title":"MSC-derived small extracellular vesicles overexpressing miR-20a promoted the osteointegration of porous titanium alloy by enhancing osteogenesis via targeting BAMBI","volume":"12","author":"Liu","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.actbio.2019.12.020","article-title":"Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126","volume":"103","author":"Liu","year":"2020","journal-title":"Acta Biomater."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e2302622","DOI":"10.1002\/advs.202302622","article-title":"Exosomal mRNAs for Angiogenic\u2013Osteogenic Coupled Bone Repair","volume":"10","author":"Ma","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Pizzicannella, J., Gugliandolo, A., Orsini, T., Fontana, A., Ventrella, A., Mazzon, E., Bramanti, P., Diomede, F., and Trubiani, O. (2019). Engineered Extracellular Vesicles From Human Periodontal-Ligament Stem Cells Increase VEGF\/VEGFR2 Expression During Bone Regeneration. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00512"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41536-025-00405-2","article-title":"Engineered BMP2\/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation","volume":"10","author":"Du","year":"2025","journal-title":"npj Regen. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"102144","DOI":"10.1016\/j.mtbio.2025.102144","article-title":"Study on VEGFA mRNA delivery via GelMA hydrogel-encapsulated extracellular vesicles for enhanced bone regeneration","volume":"34","author":"Li","year":"2025","journal-title":"Mater. Today Bio"},{"key":"ref_99","first-page":"100945","article-title":"Extracellular vesicle-functionalized bioactive scaffolds for bone regeneration","volume":"19","author":"Yu","year":"2024","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/s41551-026-01643-5","article-title":"Engineering challenges and translational opportunities in emerging gene delivery platforms","volume":"10","author":"Ma","year":"2026","journal-title":"Nat. Biomed. Eng."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/15\/1413\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T04:12:56Z","timestamp":1785989576000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/15\/1413"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":100,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cells15151413"],"URL":"https:\/\/doi.org\/10.3390\/cells15151413","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}