Impairment of microglial functions, such as phagocytosis and/or dysregulation of immune responses, has been implicated as an underlying factor involved in the pathogenesis of various neurodegenerative disorders. Our previous studies have demonstrated that long intergenic noncoding RNA (lincRNA)-Cox2 expression is influenced by nuclear factor κB (NF-κB) signaling and serves as a coactivator of transcriptional factors to regulate the expression of a vast array of immune-related genes in microglia. Extracellular vesicles (EVs) have been recognized as primary facilitators of cell-to-cell communication and cellular regulation. Herein, we show that EVs derived from astrocytes exposed to morphine can be taken up by microglial endosomes, leading, in turn, to activation of Toll-like receptor 7 (TLR7) with a subsequent upregulation of lincRNA-Cox2 expression, ultimately resulting in impaired microglial phagocytosis. This was further validated in vivo, wherein inhibition of microglial phagocytic activity was also observed in brain slices isolated from morphine-administrated mice compared with control mice. Additionally, we also showed that intranasal delivery of EVs containing lincRNA-Cox2 siRNA (small interfering RNA) was able to restore microglial phagocytic activity in mice administered morphine. These findings have ramifications for the development of EV-loaded RNA-based therapeutics for the treatment of various disorders involving functional impairment of microglia.

小胶质细胞功能受损，如吞噬作用和/或免疫反应失调，已被认为是各种神经退行性疾病发病机制中的潜在因素。我们之前的研究表明，长基因间非编码 RNA (lincRNA)-Cox2 的表达受核因子 κB (NF-κB) 信号的影响，并作为转录因子的共激活因子来调节大量免疫相关基因的表达。小胶质细胞。细胞外囊泡 (EV) 已被认为是细胞间通讯和细胞调节的主要促进剂。在此，我们表明来自暴露于吗啡的星形胶质细胞的 EV 可以被小胶质细胞核内体摄取，进而导致，激活 Toll 样受体 7 (TLR7)，随后上调 lincRNA-Cox2 表达，最终导致小胶质细胞吞噬功能受损。这进一步验证了在体内，与对照小鼠相比，在吗啡给药的小鼠脑切片中也观察到小胶质细胞吞噬活性受到抑制。此外，我们还表明，鼻内递送含有 lincRNA-Cox2 siRNA（小干扰 RNA）的 EV 能够恢复给予吗啡的小鼠的小胶质细胞吞噬活性。这些发现对开发基于 EV 的 RNA 疗法有影响，这些疗法用于治疗涉及小胶质细胞功能障碍的各种疾病。