N6-Methyladenosine (m6A) methylation plays a critical role in controlling the RNA fate. Emerging evidence has demonstrated that aberrant m6A 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 m6A methylation, the current methods suffer from the time-consuming operation and annoying off-target effect, which hampers the in situ manipulation of m6A methylation. Here, a bioorthogonal in situ modulation strategy of m6A methylation was proposed. Well-designed covalent organic framework (COF) dots (CIDM) could deprotect the agonist prodrug of m6A methyltransferase, resulting in a considerable hypermethylation of m6A modification. Simultaneously, the bioorthogonal catalyst CIDM showed oxidase (OXD)-mimic activity that further promoted the level of m6A methylation. Ultimately, the potential therapeutic effect of bioorthogonal controllable regulation of m6A methylation was demonstrated through intracellular bacteria eradication. The remarkable antimicrobial outcomes indicate that upregulating m6A 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 m6A methylation.
