You Qing, Wang Fang, Du Rong, Pi Jingnan, Wang Huayi, Huo Yue, Liu Jingyi, Wang Chen, Yu Jia, Yang Yanlian, Zhu Ling
CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China.
National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
Adv Mater. 2023 Feb;35(8):e2204910. doi: 10.1002/adma.202204910. Epub 2022 Dec 26.
N -methyladenosine (m A) modulators decide the fate of m A-modified transcripts and drive cancer development. RNA interference targeting m A 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 m A 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 m A 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.
N-甲基腺苷（m⁶A）调节剂决定了m⁶A修饰转录本的命运并推动癌症发展。靶向m⁶A调节剂的RNA干扰有望成为一种新兴的癌症治疗方法，但由于其肿瘤靶向性差和全身毒性高而具有挑战性。在此，开发了具有高CD47表达和环化精氨酸-甘氨酸-天冬氨酸（c(RGDyC)）修饰的工程化小细胞外囊泡（sEV），用于有效递送针对m⁶A阅读蛋白YTH N6-甲基腺苷RNA结合蛋白1（YTHDF1）的短干扰RNA，以通过表观遗传和免疫调节来治疗胃癌。该纳米系统通过以m⁶A依赖的方式阻碍卷曲蛋白7的翻译并使Wnt/β-连环蛋白通路失活，有效降低YTHDF1的表达并抑制胃癌的进展和转移。YTHDF1的缺失介导干扰素（IFN）-γ受体1的过表达并增强IFN-γ反应，促进肿瘤细胞上主要组织相容性复合体I类分子的表达，以实现免疫原性肿瘤细胞的自我呈递，从而刺激强烈的细胞毒性T淋巴细胞反应。工程化sEV上的CD47表达可与信号调节蛋白α竞争性结合，以增强肿瘤相关巨噬细胞对肿瘤细胞的吞噬作用。这种多功能纳米平台提供了一种高效且低毒的策略来抑制表观遗传调节因子，在促进免疫治疗方面具有巨大潜力。
