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M\u00fcller glia (MG) play pivotal roles in retinal homeostasis and disease through paracrine signaling. Small extracellular vesicles (sEVs) are bioactive nanomaterials derived from all types of live cells and are recognized as a potential strategy for neuroprotective therapy. The aim of this study is to investigate the potential roles of MG\u2010derived sEVs (MG\u2010sEVs) in a mouse model of optic nerve injury (ONC). It is found that MG\u2010sEVs treatment effectively mitigates RGC degeneration and suppresses microglial activation, thereby improves visual function in ONC mice. Retinal transcriptomic analysis reveals a strong correlation between C\u2010x3\u2010c motif chemokine ligand 1 (Cx3cl1)\u2010mediated glial activation and inflammation. Subsequently, it is confirmed that the expression levels of Cx3cl1 and proinflammatory cytokines are significantly decreased in retinas treated with MG\u2010sEVs. The components analysis of MG\u2010sEVs cargo identifies that miR\u2010125b\u20105p and miR\u201016\u20105p target Cx3cl1 gene to regulate its expression. It is also observed that Cx3cl1 colocalizes on the microglia of transgenic C\u2010x3\u2010c motif chemokine receptor 1 (Cx3Cr1)\u2010GFP mice. In conclusion, MG\u2010sEVs mitigate RGC degeneration by suppressing microglial activation via Cx3cl1\u2010Cx3cr1 signaling. This research provides additional opportunities for the treatment of RGC degeneration.<\/jats:p>","DOI":"10.1002\/adhm.202404306","type":"journal-article","created":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T05:43:09Z","timestamp":1743054189000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["M\u00fcller Glial\u2010Derived Small Extracellular Vesicles Mitigate RGC Degeneration by Suppressing Microglial Activation via Cx3cl1\u2010Cx3cr1 Signaling"],"prefix":"10.1002","volume":"14","author":[{"given":"Hai\u2010Dong","family":"Qian","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Eye Hospital of Wenzhou Medical University  Wenzhou 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang\u2010Yuan","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology Optometry and Visual 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