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While interleukin\u20103 (IL\u20103) has been reported to exert both protective and detrimental effects in neurodegenerative diseases, however, its role in \u03b1\u2010synuclein pathology remains unclear. In this study, it is found that astrocytic IL\u20103 and microglial IL\u20103R are positively responsive to \u03b1\u2010synuclein pathology in the brains of transgenic A53T Parkinson's disease (PD) mice and in an adeno\u2010associated virus (AAV)\u2010human \u03b1\u2010synuclein (AAV\u2010<jats:italic>h<\/jats:italic>\u03b1\u2010Syn)\u2010injected PD mouse model. Exogenous IL\u20103 infusion reduces behavioral abnormities and nigrostriatal \u03b1\u2010synuclein pathology. Mechanistically, IL\u20103 induces microglial phagocytosis of pathological \u03b1\u2010synuclein while simultaneously stimulating dopaminergic (DA) neurons to clear pathological \u03b1\u2010synuclein via induction of autophagy through the IFN\u2010\u03b2\/Irgm1 pathway. Due to its limited efficiency in crossing the blood\u2013brain barrier, a precise IL\u20103 delivery strategy is developed by cross\u2010linking IL\u20103 and RVG29 with PEG\u2010Linker (RVG\u2010modified IL\u20103 nanogels\u2014RVG\u2010IL3 NGs). Intravenous administration of RVG\u2010IL3 NGs shows efficient uptake by microglia and DA neurons within the brain. RVG\u2010IL3 NGs ameliorate motor deficits and pathological \u03b1\u2010synuclein by improving microglial and neuronal function in the AAV\u2010<jats:italic>h<\/jats:italic>\u03b1\u2010Syn mouse model of PD. Collectively, IL\u20103 may represent a feasible therapeutic strategy for PD.<\/jats:p>","DOI":"10.1002\/advs.202405364","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T08:36:27Z","timestamp":1725352587000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Nanotherapeutic Approaches of Interleukin\u20103 to Clear the \u03b1\u2010Synuclein Pathology in Mouse Models of Parkinson's Disease"],"prefix":"10.1002","volume":"11","author":[{"given":"Wenlong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Guangzhou Medical University  Guangzhou 510120 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Ren","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory of Nanomedicine CAS\u2010HK Joint Lab for Biomaterials Institute of Biomedicine and Biotechnology Shenzhen 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