Journal
ACS NANO
Volume 15, Issue 11, Pages 17689-17704Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c05547
Keywords
gold nanorods; acute myeloid leukemia; N6-methyadenosine; immunotherapy; tyrosine kinases inhibitors
Categories
Funding
- National Natural Science Foundation of China (NSFC) [81870117, 91959201]
- Jilin Province Science and Technology Development Plan [20190201252JC]
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Reprogramming the m(6)A landscape using gold nanorods selectively taken up by leukemia cells inhibits leukemia cell growth by disrupting redox balance and inducing ferroptosis. The nanorods abrogate endogenous m(6)A demethylase activity, leading to global m(6)A hypomethylation and post-transcriptional regulation of downstream genes. Combination treatment with the nanorods and tyrosine kinases inhibitors synergistically overcomes m(6)A-mediated TKI resistance and enhances immunotherapy outcome in leukemia.
Reprograming the N6-methyladenosine (m(6)A) landscape is a promising therapeutic strategy against recalcitrant leukemia. In this study, we synthesized gold nanorods (GNRs) of different aspect ratios using a binary surfactant mixture of hexadecyltrimethylammonium bromide and sodium oleate. Following surface functionalization with chitosan and a 12-mer peptide, GNRa-CSP12 measuring 130 x 21 nm(2) was selectively taken up by leukemia cells via targeted endocytosis. Low doses of GNRa-CSP12 inhibited the growth of leukemia cells by disrupting the redox balance and inducing ferroptosis. Mechanistically, GNRa-CSP12 abrogated endogenous Fe2+-dependent m(6)A demethylase activity, which led to global m(6)A hypomethylation and post-transcriptional regulation of downstream genes that are involved in glycolysis, hypoxia, and immune checkpoint pathways. In addition, combination treatment with GNRa-CSP12 and tyrosine kinases inhibitors (TKIs) synergistically obviated the m(6)A-mediated TKI resistance phenotype. Finally, GNRa-CSP12 as a potential immunotherapeutic agent could enhance immunotherapy outcome in leukemia. Our preclinical findings provide the proof-of-concept for targeting m(6)A-methylation-based epitranscriptomics using nanoparticle as an epigenetic drug for cancer therapy.
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