m⁶A Reader YTHDF1‐Targeting Engineered Small Extracellular Vesicles for Gastric Cancer Therapy via Epigenetic and Immune Regulation

Abstract N⁶‐methyladenosine (m⁶A) modulators decide the fate of m⁶A‐modified transcripts and drive cancer development. RNA interference targeting m⁶A modulators promise to be an emerging cancer therapy but is challenging due to its poor tumor targeting and high systematic toxicity. Here engineered small extracellular vesicles (sEVs) with high CD47 expression and cyclic arginine–glycine–aspartic (c(RGDyC)) modification are developed for effective delivery of short interfering RNA against m⁶A reader YTH N6‐methyladenosine RNA binding protein 1 (YTHDF1) to treat gastric cancer via epigenetic and immune regulation. This nanosystem efficiently depletes YTHDF1 expression and suppresses gastric cancer progression and metastasis through hampering frizzled7 translation and inactivating Wnt/β‐catenin pathway in an m⁶A dependent manner. Loss of YTHDF1 mediates overexpression of interferon (IFN)‐γ receptor 1 and enhances IFN‐γ response, promoting expression of major histocompatibility complex class I on tumor cells to achieve self‐presentation of the immunogenic tumor cells to stimulate strong cytotoxic T lymphocytes responses. CD47 expression on the engineered sEVs can competitively bind with signal regulatory protein α to enhance phagocytosis of the tumor cells by tumor‐associated macrophages. This versatile nanoplatform provides an efficient and low toxic strategy to inhibit epigenetic regulators and holds great potential in promoting immunotherapy.