A Bimetallic Metal–Organic-Framework-Based Biomimetic Nanoplatform Enhances Anti-Leukemia Immunity via Synchronizing DNA Demethylation and RNA Hypermethylation,Advanced Materials

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A Bimetallic Metal–Organic-Framework-Based Biomimetic Nanoplatform Enhances Anti-Leukemia Immunity via Synchronizing DNA Demethylation and RNA Hypermethylation
Advanced Materials ( IF 27.4 ) Pub Date : 2023-02-09 , DOI: 10.1002/adma.202210895
Yue Song ₁ , Lingxiao Zhang ₁ , Yiqiao Wang ₁ , Mingda Han ₁ , Zhihua Wang ₁ , Ning Wang ₁ , Bingru Shao ₁ , Runan Li ₁ , Kunxia Cao ₁ , Meiyu Song ₁ , Yangyang Du ₁ , Fei Yan ₁

Affiliation

Epigenetic-alterations-mediated antigenicity reducing in leukemic blasts (LBs) is one of the critical mechanisms of immune escape and resistance to T-cell-based immunotherapy. Herein, a bimetallic metal–organic framework (MOF)-based biomimetic nanoplatform (termed as AFMMB) that consists of a DNA hypomethylating agent, a leukemia stem cell (LSC) membrane, and pro-autophagic peptide is fabricated. These AFMMB particles selectively target not only LBs but also LSCs due to the homing effect and immune compatibility of the LSC membrane, and induce autophagy by binding to the Golgi-apparatus-associated protein. The autophagy-triggered dissolution of AFMMB releases active components, resulting in the restoration of the stimulator of interferon genes pathway by inhibiting DNA methylation, upregulation of major histocompatibility complex class-I molecules, and induction of RNA-methylation-mediated decay of programmed cell death protein ligand transcripts. These dual epigenetic changes eventually enhance T-cell-mediated immune response due to increased antigenicity of leukemic cells. AFMMB also can suppress growth and metastases of solid tumor, which was suggestive of a pan-cancer effect. These findings demonstrate that AFMMB may serve as a promising new nanoplatform for dual epigenetic therapy against cancer and warrants clinical validation.

中文翻译：

基于双金属金属有机框架的仿生纳米平台通过同步 DNA 去甲基化和 RNA 高甲基化增强抗白血病免疫力

白血病母细胞 (LB) 中表观遗传改变介导的抗原性降低是免疫逃逸和对基于 T 细胞的免疫疗法产生耐药性的关键机制之一。在此，制造了一种基于双金属金属有机骨架 (MOF) 的仿生纳米平台（称为 AFMMB），它由 DNA 低甲基化剂、白血病干细胞 (LSC) 膜和促自噬肽组成。由于 LSC 膜的归巢效应和免疫相容性，这些 AFMMB 颗粒不仅选择性靶向 LB，还选择性靶向 LSC，并通过与高尔基体相关蛋白结合诱导自噬。AFMMB 的自噬触发溶解释放活性成分，通过抑制 DNA 甲基化、主要组织相容性复合物 I 类分子的上调，导致干扰素基因通路刺激因子的恢复，和诱导 RNA 甲基化介导的程序性细胞死亡蛋白配体转录物的衰变。由于白血病细胞的抗原性增加，这些双重表观遗传变化最终会增强 T 细胞介导的免疫反应。AFMMB 还可以抑制实体瘤的生长和转移，这表明具有泛癌作用。这些发现表明 AFMMB 可以作为一种有前途的新型纳米平台，用于针对癌症的双重表观遗传治疗，并需要进行临床验证。

更新日期：2023-02-09

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