Zhang Shizheng, Li Mengmeng, Li Yuan, Yang Shike, Wang Jian, Ren Xiaoxiang, Wang Xiuhui, Bai Long, Huang Jianping, Geng Zhen, Han Guosheng, Fang Yibin, Su Jiacan
Department of Neurology, Wenzhou Central Hospital, Wenzhou, 325000, China.
The Second Affiliated Hospital of Shanghai University, Wenzhou, 325000, China.
J Nanobiotechnology. 2025 Mar 11;23(1):202. doi: 10.1186/s12951-025-03258-5.
Mitochondria are pivotal in sustaining oxidative balance and metabolic activity within neurons. It is well-established that mitochondrial dysfunction constitutes a fundamental pathogenic mechanism in neurodegeneration, especially in the context of Parkinson's disease (PD), this represents a promising target for therapeutic intervention. Ursodeoxycholic acid (UDCA), a clinical drug used for liver disease, possesses antioxidant and mitochondrial repair properties. Recently, it has gained attention as a potential therapeutic option for treating various neurodegenerative diseases. However, multiple barriers, including the blood-brain barrier (BBB) and cellular/mitochondrial membranes, significantly hinder the efficient delivery of therapeutic agents to the damaged neuronal mitochondria. Macrophage-derived nanovesicles (NVs), which can traverse the BBB in response to brain inflammation signals, have demonstrated promising tools for brain drug delivery. Nevertheless, natural nanovesicles inherently lack the ability to specifically target mitochondria. Herein, artificial NVs are loaded with UDCA and then functionalized with triphenylphosphonium (TPP) molecules, denoted as UDCA-NVs-TPP. These nanovesicles specifically accumulate in damaged neuronal mitochondria, reduce oxidative stress, and enhance ATP production by 42.62%, thereby alleviating neurotoxicity induced by 1-methyl-4-phenylpyridinium (MPP+). Furthermore, UDCA-loaded NVs modified with TPP successfully cross the BBB and accumulate in the striatum of PD mice. These nanoparticles significantly improve PD symptoms, as demonstrated by a 48.56% reduction in pole climb time, a 59.09% increase in hanging ability, and the restoration of tyrosine hydroxylase levels to normal, achieving remarkable therapeutic efficacy. Our work highlights the immense potential of these potent UDCA-loaded, mitochondria-targeting nanovesicles for efficient treatment of PD and other central neurodegenerative diseases.
线粒体对于维持神经元内的氧化平衡和代谢活动至关重要。众所周知，线粒体功能障碍是神经退行性疾病的一种基本致病机制，尤其是在帕金森病（PD）的背景下，这是一个有前景的治疗干预靶点。熊去氧胆酸（UDCA）是一种用于治疗肝病的临床药物，具有抗氧化和线粒体修复特性。最近，它作为治疗各种神经退行性疾病的潜在治疗选择而受到关注。然而，包括血脑屏障（BBB）和细胞/线粒体膜在内的多个障碍，显著阻碍了治疗剂向受损神经元线粒体的有效递送。巨噬细胞衍生的纳米囊泡（NVs）可以响应脑炎症信号穿过血脑屏障，已被证明是脑药物递送的有前景的工具。然而，天然纳米囊泡本质上缺乏特异性靶向线粒体的能力。在此，将人工纳米囊泡装载UDCA，然后用三苯基膦（TPP）分子进行功能化，记为UDCA-NVs-TPP。这些纳米囊泡特异性地积聚在受损的神经元线粒体中，降低氧化应激，并使ATP生成增加42.62%，从而减轻1-甲基-4-苯基吡啶鎓（MPP+）诱导的神经毒性。此外，用TPP修饰的装载UDCA的纳米囊泡成功穿过血脑屏障并积聚在PD小鼠的纹状体中。这些纳米颗粒显著改善了PD症状，爬杆时间减少48.56%，悬挂能力增加59.09%，酪氨酸羟化酶水平恢复正常，显示出显著的治疗效果。我们的工作突出了这些强大的装载UDCA、靶向线粒体的纳米囊泡在有效治疗PD和其他中枢神经退行性疾病方面的巨大潜力。
