The N6-methyladenosine (m6A) 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/m6A 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 m6A 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 m6A RNA methylation as a synergistic treatment strategy against cancer stem cells that may translate to clinical applications.
Bibliographical noteFunding Information:
This work was supported by the National Natural Science Foundation of China (NSFC; projects 82170154, 81870117, 91959201, 82004005), the Jilin Province Science and Technology Development Plan (20190201252JC) and the Foundation of Health science and Technology capacity Improvement of Jilin Province (2021JC017).
© 2022 Wiley-VCH GmbH.
- N6-methyladenosine RNA methylation
- gold nanoparticles
- leukemic stem cells
- molecular imprinting
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't