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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 m\n                    <jats:sup>6<\/jats:sup>\n                    A 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 m\n                    <jats:sup>6<\/jats:sup>\n                    A-based therapeutics and establishes a robust strategy for epigenetic reprogramming of neuroinflammation.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-75862-4","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T09:25:07Z","timestamp":1786181107000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting m6A writer METTL3 with engineered nanovesicles reduces neuroinflammation in vitro and in vivo"],"prefix":"10.1038","volume":"17","author":[{"given":"Liangfu","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanwei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanjun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"She","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-Fang","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4043-3196","authenticated-orcid":false,"given":"Zhigang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5010-0729","authenticated-orcid":false,"given":"Lang","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"75862_CR1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adx0043","volume":"388","author":"FD Shi","year":"2025","unstructured":"Shi, F. 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