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We analyzed brain-derived neurotrophic factor (BDNF) levels in serum exosomes from a diverse group of 60 individuals, including first-episode, drug-free MDD patients, medicated MDD patients, and healthy controls. Our results revealed a significant decrease in BDNF levels within MDD patients\u2019 exosomes, which notably increased post-medication, highlighting BDNF\u2019s potential as a biomarker for both MDD diagnosis and treatment efficacy. Advancing these clinical findings, we developed RVG-modified exosomes engineered to overexpress BDNF (RVG-BDNF-Exos), designed to directly target neuronal cells. Our findings demonstrate that these engineered exosomes can successfully traverse the blood\u2013brain barrier, targeting neurons in the hippocampus and prefrontal cortex. In our mouse model of depression induced by lipopolysaccharide, RVG-BDNF-Exos treatment led to a significant increase of BDNF in these key brain regions, crucial for mood regulation and neurogenesis. This intervention modulated the BDNF\/TrkB\/AKT signaling pathway, central to neural plasticity and implicated in depression\u2019s pathogenesis. Behavioral assessments exhibited substantial improvements in depressive-like behaviors in mice treated with RVG-BDNF-Exos, including reduced immobility in Tail Suspension and Forced Swim Tests. Additionally, our treatment effectively decreased neuroinflammation, as evidenced by the reduction in microglia and astrocyte numbers. Moreover, RVG-BDNF-Exos treatment enhanced neurogenesis and regulated synaptic plasticity, as indicated by the increased expression of neuronal markers MAP2 and DCX, and synaptic proteins PSD95 and Syn-1. In conclusion, this study not only underscores the clinical potential of serum exosomal BDNF as a diagnostic and therapeutic marker for MDD but also demonstrates the efficacy of RVG-BDNF-Exos in alleviating depressive symptoms. Our findings pave the way for future targeted, personalized psychiatric treatments, offering a promising direction in MDD therapy.<\/jats:p>","DOI":"10.34133\/research.0402","type":"journal-article","created":{"date-parts":[[2024,5,19]],"date-time":"2024-05-19T13:46:30Z","timestamp":1716126390000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":57,"title":["Targeted Delivery of Engineered RVG-BDNF-Exosomes: A Novel Neurobiological Approach for Ameliorating Depression and Regulating Neurogenesis"],"prefix":"10.34133","volume":"7","author":[{"given":"Shaobo","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, \rMinzu University of China, Beijing 100081, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, \rMinzu University of China, Beijing 100081, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, \rMinzu University of China, Beijing 100081, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingshan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, \rMinzu University of China, Beijing 100081, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7529-4408","authenticated-orcid":true,"given":"Yong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, \rMinzu University of China, Beijing 100081, China."},{"name":"College of Life and Environmental Sciences, \rMinzu University of China, Beijing 100081, China."},{"name":"Institute of National Security, \rMinzu University of China, Beijing 100081, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2024,7,4]]},"reference":[{"issue":"7526","key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/515180a","article-title":"Mental health: A world of depression","volume":"515","author":"Smith K","year":"2014","unstructured":"Smith K. 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