Engineered extracellular vesicles enriched with the miR ‐214/199a cluster enhance the efficacy of chemotherapy in ovarian cancer

Recurrent ovarian cancer (OC) remains a major cause of mortality due to chemoresistance and metastasis. Epigenetic aberrations, particularly dysregulated microRNA (miRNA) expression, contribute to disease progression and represent a promising therapeutic target. Here, we identify the miR‐214‐3p/miR‐199a‐5p cluster as a stage‐associated, tumor‐suppressive network that is lost in recurrent and chemoresistant OC but can be elevated using engineered small extracellular vesicles enriched with this miRNA cluster (m214‐sEVs). Using a clinically relevant mouse model that recapitulates spontaneous OC relapse following platinum‐based chemotherapy, we show that m214‐sEVs are internalized by OC cells and niche fibroblasts, leading to increased intracellular levels of this cluster and suppression of key chemoresistance‐associated pathways, including through downregulation of Toll‐like receptor 4 (TLR4), β‐catenin, and the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) protein YKT6. m214‐sEV treatment reprograms secondary tumor‐derived 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‐tumorigenic EV signaling in recurrent OC.