{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:01:19Z","timestamp":1785412879169,"version":"3.56.0"},"reference-count":30,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background:Parkinson\u2019s disease (PD) is a neurodegenerative disorder marked by motor dysfunction. No definitive methods exist to repair damaged neurons. Vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) are two neuroprotective agents that work synergistically. However, these large molecular proteins have difficulty crossing the blood\u2013brain barrier (BBB). Extracellular vesicles (EVs) offer superior targeting and low immunogenicity, making them excellent carriers. In this study we examined the protective effects of VEGF and NGF in a cell model and evaluated the therapeutic potential of VEGF\u2013NGF contained within EVs in PD rats.Methods:EVs were isolated using sequential differential centrifugation and characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blotting (WB). VEGF and NGF were loaded into the EVs using a saponin-assisted method to create VEGF@EVs, NGF@EVs, and VEGF\/NGF@EVs. The viability of 6-hydroxydopamine hydrochloride (6-OHDA)-induced SH-SY5Y cells was measured using the cell counting kit-8 assay before and after treatment with VEGF and NGF. Autophagy levels were assessed using WB, and the role of autophagy was further explored using the autophagy inhibitor chloroquine. Unilateral PD rat models were established via stereotactic injection of 6-OHDA into male Sprague\u2013Dawley rats. Behavioral changes were monitored before and after treatment. Neuronal recovery, neurotransmitter levels, and autophagy levels in the rat brains were evaluated using immunohistochemistry, enzyme-linked immunosorbent assay, and WB.Results:VEGF\/NGF@EVs significantly enhanced the viability of 6-OHDA-induced SH-SY5Y cells. A complete autophagic process was identified as essential for this protective effect. The intranasal administration of VEGF\/NGF@EVs improved motor behavior in PD rats, with performance better than that of single growth factor treatments. The number of tyrosine hydroxylase (TH)\u2013positive neurons, TH protein expression, and dopamine content were significantly increased. In addition, the level of autophagy in the rat substantia nigra was elevated.Conclusions:VEGF\/NGF@EVs exert protective effects in both in vitro and in vivo 6-OHDA-induced PD models by promoting autophagy, demonstrating greater efficacy than either growth factor alone. By transplanting VEGF\/NGF@EVs into PD rats, we showed that these vesicles can effectively cross the BBB and deliver targeted therapy to the central nervous system. This study highlights the significant potential of EV-mediated protein transplantation strategies for treating neurological disorders.<\/jats:p>","DOI":"10.31083\/jin50932","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:01:26Z","timestamp":1785409286000},"source":"Crossref","is-referenced-by-count":0,"title":["Extracellular Vesicle-Mediated Delivery of VEGF and NGF Protects Dopaminergic Neurons in 6-OHDA-Induced Parkinson\u2019s Disease Models"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4840-616X","authenticated-orcid":true,"given":"Wenyu","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Neurology, Shandong First Medical University, 250117 Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyue","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Liaocheng Hospital Affiliated to Shandong First Medical University (Liaocheng People\u2019s Hospital), 252000 Liaocheng, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Precision Key Laboratory, Liaocheng People\u2019s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, 252000 Liaocheng, Shandong, China"},{"name":"Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanfei","family":"Wei","sequence":"additional","affiliation":[{"name":"Key laboratory for Stem cell & Regenerative Medicine translation of Health Commission of Shandong Province, Liaocheng Hospital Affiliated to Shandong First Medical University (Liaocheng People\u2019s Hospital), 252000 Liaocheng, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabin","family":"Han","sequence":"additional","affiliation":[{"name":"Key laboratory for Stem cell & Regenerative Medicine translation of Health Commission of Shandong Province, Liaocheng Hospital Affiliated to Shandong First Medical University (Liaocheng People\u2019s Hospital), 252000 Liaocheng, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueli","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Liaocheng Hospital Affiliated to Shandong First Medical University (Liaocheng People\u2019s Hospital), 252000 Liaocheng, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. 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