Reprograming the N6-methyladenosine (m6A) 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 × 21 nm2 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 m6A demethylase activity, which led to global m6A 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 m6A-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 m6A-methylation-based epitranscriptomics using nanoparticle as an "epigenetic drug"for cancer therapy.
Bibliographical noteFunding Information:
This work was supported by the National Natural Science Foundation of China (NSFC; projects 81870117 and 91959201) and the Jilin Province Science and Technology Development Plan (20190201252JC).
- acute myeloid leukemia
- gold nanorods
- tyrosine kinases inhibitors
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't