Regulating Tumor N6‐Methyladenosine Methylation Landscape using Hypoxia‐Modulating OsSx Nanoparticles

The epigenetic dysregulation and hypoxia are two important factors that drive tumor malignancy, and N6‐methyladenosine (m6A) in mRNA is involved in the regulation of gene expression. Herein, a nanocatalyst OsSx‐PEG (PEG = poly(ethylene glycol)) nanoparticles (NPs) as O2 modulator is developed to improve tumor hypoxia. OsSx‐PEG NPs can significantly downregulate genes involved in hypoxia pathway. Interestingly, OsSx‐PEG NPs elevate RNA m6A methylation levels to cause the m6A‐dependent mRNA degradation of the hypoxia‐related genes. Moreover, OsSx‐PEG NPs can regulate the expression of RNA m6A methyltransferases and demethylases. Finally, DOX@OsSx‐PEG (DOX = doxorubicin; utilized as a model drug) NPs modulate tumor hypoxia and regulate mRNA m6A 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. Modified OsSx catalytic nanoparticles (NPs) are developed as drug carriers for combined chemo‐photothermal therapy with multi‐model imaging. OsSx‐PEG NPs can catalyze decomposition of H2O2 to produce O2 to modulate hypoxia and enhance drug sensitivity. Moreover, OsSx‐PEG NPs can cause mRNA degradation of hypoxia‐related genes by regulating RNA m6A methylation levels.