Gold Nanorods Exhibit Intrinsic Therapeutic Activity via Controlling <i>N</i>6‑Methyladenosine-Based Epitranscriptomics in Acute Myeloid Leukemia

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.