RVG修饰的间充质干细胞外泌体通过转变小胶质细胞极性治疗强迫症OA

[Objective]This study aimed to investigate the therapaeutic effects of rabies virus glycoprotein(RVG)-modified mesenchymal stem cell-derived exosomes(MSC-EXO)in a mouse model of obsessive-compulsive disorder(OCD),and to explore the underlying mechanisms.[Methods]Primary mouse adipose-derived MSCs were isolated and characterized by adipogenic and osteogenic differentiation assays and flow cytometry.RVG-overexpressing MSCs were generated,and the derived exosomes were characterized by nanoparticle size analysis,Western blotting,and transmission electron microscopy.An OCD mouse model was established using quinpirole,and the mice were divided into five groups:control,model,clomipramine(CMI),MSC-EXO,and RVG-MSC-EXO.Compulsive-like behaviors and cognitive function were evaluated using the compulsive checking test,open field test,marble-burying tes,and Morris water maze.The levels of inflammatory cytokines in the mouse prefrontal cortex were measured by qPCR and ELISA.Microglial polarization in the prefrontal cortex was assessed by immunofluorescence staining.The brain-targeting ability of RVG-MSC-EXO was verified using an in vivo imaging system(IVIS).[Results]RVG-modified MSC-derived exosomes exhibited significant brain-targeting ability in mice.Exosome treatment significantly reduced compulsive checking and marble-burying behaviors in mice.Exosome treatment decreased pro-inflammatory cytokines and increased anti-inflammatory cytokines.Exosome treatment promoted a shift in microglial polarization from the M1 phenotype to M2 phenotype.[Conclusion]RVG-modified mesenchymal stem cell-derived exosomes can target the mouse brain,alleviate neuroinflammation by promoting microglial polarization towards the M2 phenotype,and ultimately reduce compulsive-like behaviors in OCD mice.