In situ bioorthogonal-modulation of m6A RNA methylation in macrophages for efficient eradication of intracellular bacteria

Abstract

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.