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In the cornea, sensory nerves are critical for maintaining epithelial integrity and ocular homeostasis. Nerve injury resulting from trauma, surgery, or disease leads to persistent epithelial defects and impaired vision, with limited treatment options. Here, the neuro\u2010regenerative potential of mesenchymal stem cell\u2010derived EVs (MSC\u2010EVs) isolated from human cornea (Co\u2010MSC) and bone marrow (BM\u2010MSC) cultured under 2D and 3D conditions is investigated. EVs are characterized by nanoparticle tracking analysis, ExoView profiling, and Western blot, and their effects on nerve regeneration are evaluated using primary trigeminal ganglion neurons in vitro and a murine corneal injury model in vivo. EVs from both tissue sources promoted neurite outgrowth; however, 3D\u2010derived EVs demonstrate superior efficacy compared to 2D\u2010derived EVs in vitro and in vivo. Co\u2010MSC\u2010EVs show a consistent trend toward enhanced regenerative effects over BM\u2010MSC\u2010EVs. Small RNA sequencing reveals that EV cargo is influenced by both tissue origin and culture dimensionality, with Co\u2010MSC\u2010EVs enriched in miRNAs regulating the extracellular matrix and immune pathways, while BM\u2010MSC\u2010EVs are enriched in neurotrophic signaling miRNAs. These findings support the rational design of MSC\u2010EV\u2010based therapies for neuro\u2010ophthalmic repair.<\/jats:p>","DOI":"10.1002\/smll.202507451","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T07:52:01Z","timestamp":1764834721000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Corneal Nerve Regeneration via MSC\u2010Derived EVs: Tissue Source and Culture Dimensionality Dictate miRNA Cargo and Therapeutic Efficacy"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3807-8175","authenticated-orcid":false,"given":"Hamed","family":"Massoumi","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences Illinois Eye and Ear Infirmary. University of Illinois Chicago  Chicago IL 60612 USA"},{"name":"Richard and Loan Hill Department of Biomedical Engineering University of Illinois Chicago  Chicago IL 60607 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eitan A.","family":"Katz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences Illinois Eye and Ear Infirmary. University of Illinois Chicago  Chicago IL 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Alviar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences Illinois Eye and Ear Infirmary. University of Illinois Chicago  Chicago IL 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences Illinois Eye and Ear Infirmary. 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University of Illinois Chicago  Chicago IL 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine University of Illinois Chicago  Chicago Illinois 606012 USA"},{"name":"University of Illinois Cancer Center  Chicago Illinois 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine University of Illinois Chicago  Chicago Illinois 606012 USA"},{"name":"University of Illinois Cancer Center  Chicago Illinois 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor H.","family":"Guaiquil","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences Illinois Eye and Ear Infirmary. 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