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

Kunxia Cao; Yangyang Du; Xin Bao; Mingda Han; Rui Su; Jiuxia Pang; Shujun Liu; Zhan Shi; Fei Yan; Shouhua Feng

doi:10.1002/smll.202106558

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

Small. 2022 Apr;18(13):e2106558. doi: 10.1002/smll.202106558. Epub 2022 Feb 4.

Authors

Kunxia Cao¹, Yangyang Du¹, Xin Bao², Mingda Han¹, Rui Su¹, Jiuxia Pang³, Shujun Liu³, Zhan Shi¹, Fei Yan¹, Shouhua Feng¹

Affiliations

¹ State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), International Research Center for Chemistry-Medicine Joint Innovation, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun, 130012, China.
² Department of Thyroid, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, China.
³ The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA.

PMID: 35119204
DOI: 10.1002/smll.202106558

Abstract

The N6-methyladenosine (m⁶ 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/m⁶ 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 m⁶ 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 m⁶ A RNA methylation as a synergistic treatment strategy against cancer stem cells that may translate to clinical applications.

Keywords: N6-methyladenosine RNA methylation; glutathione; gold nanoparticles; leukemic stem cells; molecular imprinting.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives
Alpha-Ketoglutarate-Dependent Dioxygenase FTO* / genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO* / metabolism
Glutathione
Nanoparticles*
Neoplastic Stem Cells
RNA, Messenger / genetics

Substances

RNA, Messenger
N-methyladenosine
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Glutathione
Adenosine