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. 2025 May;14(12):e2404306.
doi: 10.1002/adhm.202404306. Epub 2025 Mar 25.

Müller Glial-Derived Small Extracellular Vesicles Mitigate RGC Degeneration by Suppressing Microglial Activation via Cx3cl1-Cx3cr1 Signaling

Hai-Dong Qian  1 , Xiang-Yuan Song  1 , Guan-Wen He  1 , Xue-Ni Peng  1 , Ying Chen  1 , Pan Huang  1 , Jing Zhang  1 , Xiao-Yan Lin  1 , Qiao Gao  1 , Sen-Miao Zhu  1 , Tong Li  1 , Zai-Long Chi  1   2
Affiliations

Müller Glial-Derived Small Extracellular Vesicles Mitigate RGC Degeneration by Suppressing Microglial Activation via Cx3cl1-Cx3cr1 Signaling

Hai-Dong Qian et al. Adv Healthc Mater. 2025 May.

Abstract

Retinal ganglion cell (RGC) degeneration leads to irreversible blindness. Müller 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-derived sEVs (MG-sEVs) in a mouse model of optic nerve injury (ONC). It is found that MG-sEVs 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-x3-c motif chemokine ligand 1 (Cx3cl1)-mediated 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-sEVs. The components analysis of MG-sEVs cargo identifies that miR-125b-5p and miR-16-5p target Cx3cl1 gene to regulate its expression. It is also observed that Cx3cl1 colocalizes on the microglia of transgenic C-x3-c motif chemokine receptor 1 (Cx3Cr1)-GFP mice. In conclusion, MG-sEVs mitigate RGC degeneration by suppressing microglial activation via Cx3cl1-Cx3cr1 signaling. This research provides additional opportunities for the treatment of RGC degeneration.

Keywords: Cx3cl1‐Cx3cr1 signaling; RGC degeneration; inflammation; microglia; müller glia; small extracellular vesicles (sEVs).

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