Engineered Extracellular Vesicles Enriched with miR-214 Enhance the Efficacy of Chemotherapy for Ovarian Cancer

Recurrent ovarian cancer (OC) remains a major cause of mortality due to chemoresistance and metastasis. Epigenetic dysfunction, particularly involving microRNAs (miRNAs), contributes to disease progression. Extracellular vesicles (EVs) are key modulators of tumor epigenetic profiles by delivering bioactive cargo to recipient cells. Here, we demonstrate that engineered small EVs derived from cerebral endothelial cells and enriched with miR-214-3p (m214-sEVs) enhance chemosensitivity, suppress tumor growth, and improve survival when combined with carboplatin. Using a clinically relevant mouse model that mimics spontaneous OC relapse following first-line platinum-based chemotherapy, we showed that m214-sEVs were internalized by OC cells and the OC niche fibroblasts via clathrin-mediated endocytosis, resulting in the elevation of miR-214-3p/miR-199a-5p and the downregulation of chemoresistance-associated genes, including toll-like receptor 4 (TLR4), β-catenin, and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein YKT6. Moreover, secondary tumor-derived sEVs (t-sEVs) released by OC and niche cells that internalized m214-sEVs reduced pro-metastatic proteins, such as integrin β1 and matrix metalloproteinase 9 (MMP9), in their cargo and limited their capacity to promote invasion and resistance. In vitro, YKT6 overexpression in ovarian cancer stem cells (OCSCs) attenuated the effect of m214-sEVs on sensitizing carboplatin to block OCSC migration. These findings support the translational potential of miRNA-loaded sEVs (m214-sEVs) as a therapeutic strategy to overcome chemoresistance and recurrence in OC.