Glutathione-Bioimprinted Nanoparticles Targeting of N6-methyladenosine FTO Demethylase as a Strategy against Leukemic Stem Cells

被引：83

作者：

Cao, Kunxia ^{[1
]}

Du, Yangyang ^{[1
]}

Bao, Xin ^{[2
]}

Han, Mingda ^{[1
]}

Su, Rui ^{[1
]}

Pang, Jiuxia ^{[3
]}

Liu, Shujun ^{[3
]}

Shi, Zhan ^{[1
]}

Yan, Fei ^{[1
]}

Feng, Shouhua ^{[1
]}

机构：

[1] Jilin Univ, Coll Chem, Int Res Ctr Chem Med Joint Innovat,State Key Lab, Int Joint Res Lab Nanomicro Architecture Chem NMA, 2699 Qianjin St, Changchun 130012, Peoples R China

[2] Second Hosp Jilin Univ, Dept Thyroid, 218 Zigiang St, Changchun 130041, Peoples R China

[3] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA

来源：

SMALL | 2022年 / 18卷 / 13期

基金：

中国国家自然科学基金;

关键词：

glutathione; gold nanoparticles; leukemic stem cells; molecular imprinting; N6-methyladenosine RNA methylation; ACUTE MYELOID-LEUKEMIA; RNA; M(6)A;

D O I：

10.1002/smll.202106558

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The N6-methyladenosine (m(6)A) demethylase FTO plays an oncogenic role in acute myeloid leukemia (AML). Despite the promising recent progress for developing some small-molecule FTO inhibitors, the clinical potential remains limited due to mild biological function, toxic side effects and low sensitivity and/or specificity to leukemic stem cells (LSCs). Herein, FTO inhibitor-loaded GSH-bioimprinted nanocomposites (GNPIPP12MA) are developed that achieves targeting of the FTO/m(6)A pathway synergized GSH depletion for enhancing anti-leukemogenesis. GNPIPP12MA can selectively target leukemia blasts, especially LSCs, and induce ferroptosis by disrupting intracellular redox status. In addition, GNPIPP12MA increases global m(6)A RNA modification and decreases the transcript levels in LSCs. GNPIPP12MA augments the efficacy of the PD-L1 blockade by increasing the infiltration of cytotoxic T cells for enhanced anti-leukemia immunity. This study offers insights for a GSH-bioimprinted nanoplatform targeting m(6)A RNA methylation as a synergistic treatment strategy against cancer stem cells that may translate to clinical applications.

引用

页数：12

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