Parkinson’s disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available. MicroRNA-124 has been regarded as a promising therapeutic entity for Parkinson’s disease due to its pro-neurogenic and neuroprotective roles. However, its efficient delivery to the brain remains challenging. Here, we used umbilical cord blood mononuclear cell-derived extracellular vesicles as a biological vehicle to deliver microRNA (miR)-124-3p and evaluate its therapeutic effects in a mouse model of Parkinson’s disease. In vitro, miR-124-3p-loaded small extracellular vesicles induced neuronal differentiation in subventricular zone neural stem cell cultures and protected N27 dopaminergic cells against 6-hydroxydopamine-induced toxicity. In vivo, intracerebroventricularly administered small extracellular vesicles were detected in the subventricular zone lining the lateral ventricles and in the striatum and substantia nigra, the brain regions most affected by the disease. Most importantly, although miR-124-3p-loaded small extracellular vesicles did not increase the number of new neurons in the 6-hydroxydopamine-lesioned striatum, the formulation protected dopaminergic neurons in the substantia nigra and striatal fibers, which fully counteracted motor behavior symptoms. Our findings reveal a novel promising therapeutic application of small extracellular vesicles as delivery agents for miR-124-3p in the context of Parkinson’s disease.

帕金森病是一种神经退行性疾病，其特征是黑质中多巴胺能神经元的丧失，并且没有有效的治疗方法。MicroRNA-124 由于其促神经发生和神经保护作用而被认为是帕金森病的有前途的治疗实体。然而，将其有效输送到大脑仍然具有挑战性。在这里，我们使用脐带血单核细胞来源的细胞外囊泡作为生物载体来递送 microRNA (miR)-124-3p 并评估其在帕金森病小鼠模型中的治疗效果。在体外，负载 miR-124-3p 的小细胞外囊泡诱导室下区神经干细胞培养物中的神经元分化，并保护 N27 多巴胺能细胞免受 6-羟基多巴胺诱导的毒性。在体内，在侧脑室衬里的室下区以及受疾病影响最严重的大脑区域纹状体和黑质中检测到脑室内注射的小细胞外囊泡。最重要的是，虽然负载 miR-124-3p 的小细胞外囊泡没有增加 6-羟基多巴胺损伤纹状体中新神经元的数量，但该制剂保护了黑质和纹状体纤维中的多巴胺能神经元，从而完全抵消了运动行为症状。我们的研究结果揭示了小细胞外囊泡作为 miR-124-3p 递送剂在帕金森病中的一种新的有前景的治疗应用。