bioorthogonal-modulation of mA RNA methylation in macrophages for efficient eradication of intracellular bacteria.

N-Methyladenosine (mA) methylation plays a critical role in controlling the RNA fate. Emerging evidence has demonstrated that aberrant mA methylation in immune cells such as macrophages could alter cell homeostasis and function, which can be a promising target for disease treatment. Despite tremendous progress in regulating the level of mA methylation, the current methods suffer from the time-consuming operation and annoying off-target effect, which hampers the manipulation of mA methylation. Here, a bioorthogonal modulation strategy of mA methylation was proposed. Well-designed covalent organic framework (COF) dots (CIDM) could deprotect the agonist prodrug of mA methyltransferase, resulting in a considerable hypermethylation of mA modification. Simultaneously, the bioorthogonal catalyst CIDM showed oxidase (OXD)-mimic activity that further promoted the level of mA methylation. Ultimately, the potential therapeutic effect of bioorthogonal controllable regulation of mA methylation was demonstrated through intracellular bacteria eradication. The remarkable antimicrobial outcomes indicate that upregulating mA methylation in macrophages could reprogram them into the M1 phenotype with high bactericidal activity. We believe that our bioorthogonal chemistry-controlled epigenetics regulatory strategy will provide a unique insight into the development of controllable mA methylation.