Liuyan Ding, Yuchen Xiao, Zongtang Xu, Ziting Zhu, Tingting Gan, Xingting Huang, Hui Shu, Xiaolei Liang, Mingshu Mo, Xiaoyun Huang, Xiaoqin Zhu, Weiqing Huang, Pingyi Xu, Wenlong Zhang
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons. The development of effective neuroprotective therapies is severely hampered by the blood-brain barrier (BBB), which restricts drug delivery to the central nervous system. This study aimed to develop a novel brain-targeted nanodelivery system by functionalizing extracellular vesicles (EVs) with a rabies virus glycoprotein (RVG)-derived peptide to deliver echinatin (Echi), and to systematically evaluate its therapeutic efficacy and underlying mechanisms in a mouse model of PD. RESULTS: We successfully engineered the nanotherapeutics, termed RVG-EVs@Echi, which efficiently crossed the BBB and selectively accumulated in DA neurons and microglia following systemic administration. In a chronic MPTP-induced mouse model of PD, treatment with RVG-EVs@Echi significantly ameliorated motor deficits and rescued tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and striatum, with no detectable peripheral toxicity. Mechanistically, RVG-EVs@Echi exerted potent neuroprotective effects by upregulating insulin-like growth factor-2 (IGF-2) and activating the downstream PI3K/Akt/Nrf2 signaling cascade, which mitigated oxidative stress and neuronal apoptosis. Furthermore, integrated multi-omics analyses revealed that RVG-EVs@Echi treatment modulated metabolic profiles in the midbrain and gut, and partially restored MPTP-induced gut microbiota dysbiosis. CONCLUSIONS: This study demonstrates that RVG-EVs@Echi represents a safe, noninvasive, and effective nanotherapeutic platform for targeted brain delivery in PD. By activating the IGF-2/PI3K/Akt/Nrf2 neuroprotective pathway and modulating the gut-brain metabolic axis, this targeted delivery system presents a highly promising and translatable strategy for the treatment of PD and other neurodegenerative diseases.