Targeted Delivery of Engineered RVG-BDNF-Exosomes: A Novel Neurobiological Approach for Ameliorating Depression and Regulating Neurogenesis

Author:

Liu Shaobo1,Chen Lei1,Guo Mei1,Li Yongbiao,Liu Qingshan1,Cheng Yong123ORCID

Affiliation:

1. Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, Minzu University of China, Beijing 100081, China.

2. College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China.

3. Institute of National Security, Minzu University of China, Beijing 100081, China.

Abstract

Addressing the urgent need for innovative depression treatments, this study heralds a breakthrough in major depressive disorder (MDD) therapy by intertwining clinical observations with neurobiological advancements. 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’ exosomes, which notably increased post-medication, highlighting BDNF’s 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–brain 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’s 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.

Funder

National Natural Science Foundation of China

Publisher

American Association for the Advancement of Science (AAAS)

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