Epigenetic-targeted biomimetic nanomedicine modulates epithelial mesenchymal transition to enhance chemosensitivity in heterogeneous tumors

Abstract

Epithelial-mesenchymal transition (EMT) is a key driver of chemoresistance and poor clinical outcomes in cancer. Strategies to reverse EMT-mediated drug resistance and to dynamically monitor treatment response are critical for improving therapeutic efficacy. Previous studies have implicated METTL3-regulated N⁶-methyladenosine (m⁶A) methylation in promoting EMT and tumor progression,highlighting its potential as a therapeutic target. Here, we develop a glutathione-responsive biomimetic nanomedicine (termed ACVS) that encapsulates METTL3 inhibitors within tumor-targeting cell membrane vesicles for controlled drug release. ACVS effectively reverse EMT phenotypes in vitro in transforming growth factor-β (TGF-β)-induced EMT cell models and restory chemosensitivity to standard therapeutics. In vivo validation in tumor-bearing mice and patient-derived circulating tumor cells (CTCs) further demonstrate that METTL3 inhibition enhance tumor suppression when combine with chemotherapy. To dynamically assess the relationship between EMT and chemoresistance, we implement single-cell resolution in situ mRNA profiling, which revealed spatial heterogeneity in EMT marker expression correlated with drug response. These findings propose a combinatorial strategy to overcome chemoresistance through METTL3-targeted modulation of EMT, while providing a methodological framework for real-time treatment monitoring in personalized oncology.

Keywords: Biomimetic nanomedicine; Chemoresistance; Circulating tumor cells; Controlled drug release; Epithelial–mesenchymal transition; N(6)-methyladenosine.