Regulating Tumor <i>N</i><sup>6</sup>‐Methyladenosine Methylation Landscape using Hypoxia‐Modulating OsS<i><sub>x</sub></i> Nanoparticles
Yue Zheng, Yu‐Yi Ling, Dongyang Zhang, Cai‐Ping Tan, Hang Zhang, Gang Yang, Hongsheng Wang, Liang‐Nian Ji, Zong‐Wan Mao
Abstract
Abstract The epigenetic dysregulation and hypoxia are two important factors that drive tumor malignancy, and N 6 ‐methyladenosine (m 6 A) in mRNA is involved in the regulation of gene expression. Herein, a nanocatalyst OsS x ‐PEG (PEG = poly(ethylene glycol)) nanoparticles (NPs) as O 2 modulator is developed to improve tumor hypoxia. OsS x ‐PEG NPs can significantly downregulate genes involved in hypoxia pathway. Interestingly, OsS x ‐PEG NPs elevate RNA m 6 A methylation levels to cause the m 6 A‐dependent mRNA degradation of the hypoxia‐related genes. Moreover, OsS x ‐PEG NPs can regulate the expression of RNA m 6 A methyltransferases and demethylases. Finally, DOX@OsS x ‐PEG ( DOX = doxorubicin; utilized as a model drug) NPs modulate tumor hypoxia and regulate mRNA m 6 A methylation of hypoxia‐related genes in vivo. As the first report about relationship between catalytic nanomaterials and RNA modifications, the research opens a new avenue for unveiling the underlying action mechanisms of hypoxia‐modulating nanomaterials and shows potential of regulating RNA modification to overcome chemoresistance.