Sul Jae Hoon, Shin Sol, Kim Hark Kyun, Han Jihoon, Kim Junsik, Son Soyong, Lee Jungmi, Baek Seung Hyun, Cho Yoonsuk, Lee Jeongmi, Park Jinsu, Ahn Donghoon, Park Sunyoung, Palomera Leon F, Lim Jeein, Kim Jongho, Kim Chanhee, Han Seungsu, Chung Ka Young, Lee Sangho, Kam Tae-In, Lee Yunjong, Kim Jeongyun, Park Jae Hyung, Jo Dong-Gyu
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, Republic of Korea.
J Extracell Vesicles. 2024 Dec;13(12):e70018. doi: 10.1002/jev2.70018.
The application of extracellular vesicles (EVs) as vehicles for anti-Parkinson's agents represents a significant advance, yet their clinical translation is hampered by challenges in efficient brain delivery and complex blood-brain barrier (BBB) targeting strategies. In this study, we engineered dopamine onto the surface of adipose-derived stem cell EVs (Dopa-EVs) utilizing a facile, two-step cross-linking approach. This engineering enhanced neuronal uptake of the EVs in primary neurons and neuroblastoma cells, a process shown to be competitively inhibited by dopamine pretreatment and dopamine receptor antibodies. Notably, Dopa-EVs demonstrated increased brain accumulation in mouse Parkinson's disease (PD) models. Therapeutically, Dopa-EVs administration led to the rescue of dopaminergic neuronal loss and amelioration of behavioural deficits in both 6-hydroxydopamine (6-OHDA) and α-Syn PFF-induced PD models. Furthermore, we observed that Dopa-EVs stimulated autophagy evidenced by the upregulation of Beclin-1 and LC3-II. These findings collectively indicate that surface modification of EVs with dopamine presents a potent strategy for targeting dopaminergic neurons in the brain. The remarkable therapeutic potential of Dopa-EVs, demonstrated in PD models, positions them as a highly promising candidate for PD treatment, offering a significant advance over current therapeutic modalities.
将细胞外囊泡(EVs)用作抗帕金森病药物的载体是一项重大进展,然而其临床转化受到高效脑内递送挑战以及复杂的血脑屏障(BBB)靶向策略的阻碍。在本研究中,我们利用一种简便的两步交联方法将多巴胺工程化到脂肪来源干细胞外囊泡(Dopa-EVs)的表面。这种工程化增强了原代神经元和神经母细胞瘤细胞对EVs的神经元摄取,多巴胺预处理和多巴胺受体抗体竞争性抑制了这一过程。值得注意的是,Dopa-EVs在小鼠帕金森病(PD)模型中显示出脑内蓄积增加。在治疗方面,给予Dopa-EVs可挽救6-羟基多巴胺(6-OHDA)和α-突触核蛋白原纤维(α-Syn PFF)诱导的PD模型中的多巴胺能神经元损失,并改善行为缺陷。此外,我们观察到Dopa-EVs刺激自噬,这通过Beclin-1和LC3-II的上调得以证明。这些发现共同表明,用多巴胺对EVs进行表面修饰是一种靶向脑内多巴胺能神经元的有效策略。Dopa-EVs在PD模型中显示出的显著治疗潜力使其成为PD治疗极具前景的候选者,相较于目前的治疗方式有了重大进展。
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