Dual-functional extracellular vesicles enable synergistic treatment via m⁶A reader YTHDF1-targeting epigenetic regulation and chemotherapy

Chemotherapy remains one of the most prevailing strategies for cancer treatment. However, its treatment effect is hampered by drug resistance, nonspecific tumor targeting, and severe toxic side effects. Combination chemotherapy with synergistic effect has become an attractive tumor therapy. N⁶-methyladenosine (m⁶A) regulators determine the fate of m⁶A-modified transcripts and play vital roles in cancer development and drug resistance. Gene therapy such as small interfering RNA (siRNA) is a promising strategy to reduce the abnormal gene expression of m⁶A regulators. However, its poor selectivity and high systemic toxicity necessitate the use of delivery vectors to target specific cells and tissues. Here, we constructed a dual-functional targeted nanodrug platform for the synergetic m⁶A-associated epigenetic regulation and chemotherapy of ovarian cancer. We encapsulated siRNA targeting the m⁶A reader YT521-B homology (YTH) N⁶-methyladenosine RNA-binding protein 1 (YTHDF1) and docetaxel (DTX), the first-line chemotherapeutic agent of ovarian cancer, into mesenchymal stem cell-derived small extracellular vesicles (MsEVs). This nanosystem exhibits significant tumor targeting and endo/lysosomal escape of siYTHDF1. It effectively depletes YTHDF1 and suppresses the protein translation of eukaryotic translation initiation factor 3 subunit C (EIF3C) in an m⁶A-dependent manner. The combination of YTHDF1-targeting epigenetic regulation significantly enhances the anti-tumor effect of DTX and effectively inhibits ovarian cancer progression without causing significant systemic toxicity. This co-delivery nanoplatform offers a promising approach for combinational cancer treatment, showing improved anti-tumor efficacy through the synergistic effects of epigenetic regulation and chemotherapeutic inhibition.