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Epigenetic aberrations, particularly dysregulated microRNA (miRNA) expression, contribute to disease progression and represent a promising therapeutic target. Here, we identify the miR\u2010214\u20103p\/miR\u2010199a\u20105p cluster as a stage\u2010associated, tumor\u2010suppressive network that is lost in recurrent and chemoresistant OC but can be elevated using engineered small extracellular vesicles enriched with this miRNA cluster (m214\u2010sEVs). Using a clinically relevant mouse model that recapitulates spontaneous OC relapse following platinum\u2010based chemotherapy, we show that m214\u2010sEVs are internalized by OC cells and niche fibroblasts, leading to increased intracellular levels of this cluster and suppression of key chemoresistance\u2010associated pathways, including through downregulation of Toll\u2010like receptor 4 (TLR4), \u03b2\u2010catenin, and the soluble N\u2010ethylmaleimide\u2010sensitive factor attachment protein receptor (SNARE) protein YKT6. m214\u2010sEV treatment reprograms secondary tumor\u2010derived sEVs toward a less prometastatic cargo profile and decreases carboplatin resistance and cell migration. Enforced YKT6 overexpression abrogates these effects, establishing YKT6 as a key downstream effector. Collectively, these findings support engineered sEVs as a translatable strategy to overcome chemoresistance and disrupt pro\u2010tumorigenic EV signaling in recurrent OC.<\/jats:p>","DOI":"10.1002\/1878-0261.70224","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:43:07Z","timestamp":1770986587000},"page":"2220-2242","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Engineered extracellular vesicles enriched with the\n                    <scp>miR<\/scp>\n                    \u2010214\/199a cluster enhance the efficacy of chemotherapy in ovarian cancer"],"prefix":"10.1002","volume":"20","author":[{"given":"Weida","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology Henry Ford Hospital  Detroit MI USA"},{"name":"Department of Physiology, College of Human Medicine Michigan State University  Lansing MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayesha","family":"Alvero","sequence":"additional","affiliation":[{"name":"C.S. 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