Abstract

Epigenetic editing, particularly N⁶-methyladenosine (m⁶A) modification, represents a promising therapeutic strategy by silencing genes without altering DNA sequence. However, in vivo epigenetic intervention of neuroinflammation remains challenging and has rarely been explored. Here we developed a hybrid epigenetic nanomodulator, siMETTL3-hNVs, by integrating natural microglia-derived nanovesicles (NVs) with synthetic liposomes pre-loading small interfering RNA targeting the m⁶A writer methyltransferase-like 3 (METTL3). Natural NVs enabled siMETTL3-hNVs to achieve inflamed-brain delivery through CCR2-CCL2 chemotaxis and caveolae-mediated transcytosis across the blood-brain barrier. More importantly, relying on abundant cytokine receptors on the NVs, siMETTL3-hNVs served as decoys to neutralize pro-inflammatory cytokines, synergizing with the intracellular silencing of METTL3 to drive microglial M2 repolarization. In female mouse models of acute neuroinflammation and radiation-induced brain injury, siMETTL3-hNVs treatment significantly reduced cytokine levels, attenuated hippocampal damage, and ameliorated cognitive deficits. This work overcomes critical delivery bottlenecks in m6A-based therapeutics and establishes a robust strategy for epigenetic reprogramming of neuroinflammation.

Title

Targeting m6A writer METTL3 with engineered nanovesicles reduces neuroinflammation in vitro and in vivo

Authors

Liangfu Xu (徐良富), Yuanwei Pan (潘远伟), Guanjun Li (李冠俊), Peng She (佘鹏), Qian-Fang Meng (孟倩芳), Zhigang Liu (刘志刚) & Lang Rao (饶浪)

Journal Information

Nature Communications (2026)

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