Jian Chuyao, Hong Yigen, Liu Hongsheng, Yang Qinglu, Zhao Shaofeng
Department of Rehabilitation Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
Guangdong Huayi Biomedical Science and Technology Center, Guangzhou, Guangdong, China.
Int J Pharm. 2025 Jan 25;669:125087. doi: 10.1016/j.ijpharm.2024.125087. Epub 2024 Dec 14.
Ischemic stroke (IS), a prevalent cerebrovascular disorder, is characterized by high morbidity rates and significant disability. However, relevant drug therapy for IS still suffers from limitations such as limited blood-brain barrier (BBB) penetration efficiency, single therapeutic target, short half-life, and strong side effects. The development of multi-target neuroprotective agents using natural drug molecules with low toxicity and combining them with nanotechnology to improve BBB permeability and drug utilization is an important direction in the development of IS therapeutic strategies. Based on the anti-inflammatory and antioxidant properties of quercetin (Que), as well as the ROS-responsive degradation properties of polydopamine (PDA), an IS therapeutic strategy (Que@DAR NPs) was developed in this study. Que@DAR NPs were formed by dopamine wrapping Que by oxidative self-assembly and wrapping the rabies virus glycoprotein (RVG29) on the surface. The results showed that Que@DAR NPs greatly improved the dispersion stability of Que and exhibited ROS-responsive degradation properties. Cellular internalization assay in human neuroblastoma cells (SH-SY5Y) showed that RVG29 peptide substantially augmented the cellular uptake of Que@DAR NPs. Moreover, Que@DAR NPs can effectively reduce the oxidative damage of SH-SY5Y cells and induce the polarization of microglia to anti-inflammatory (M2) phenotype. In vivo studies further demonstrated that Que@DAR NPs inhibited neuroinflammation, reduced neuronal apoptosis, and significantly ameliorated neurological dysfunction in a rat model of middle cerebral artery occlusion (MCAO). In conclusion, Que@DAR NPs provide a safe and effective new strategy for the precision treatment of IS.
缺血性中风（IS）是一种常见的脑血管疾病，具有高发病率和显著的致残性。然而，针对IS的相关药物治疗仍存在局限性，如血脑屏障（BBB）穿透效率有限、治疗靶点单一、半衰期短和副作用强等。利用低毒天然药物分子开发多靶点神经保护剂，并将其与纳米技术相结合以提高BBB通透性和药物利用率，是IS治疗策略发展的一个重要方向。基于槲皮素（Que）的抗炎和抗氧化特性，以及聚多巴胺（PDA）的活性氧（ROS）响应降解特性，本研究开发了一种IS治疗策略（Que@DAR NPs）。Que@DAR NPs是通过多巴胺氧化自组装包裹Que，并在表面包裹狂犬病病毒糖蛋白（RVG29）形成的。结果表明，Que@DAR NPs大大提高了Que的分散稳定性，并表现出ROS响应降解特性。在人神经母细胞瘤细胞（SH-SY5Y）中的细胞内化试验表明，RVG29肽显著增强了Que@DAR NPs的细胞摄取。此外，Que@DAR NPs可以有效降低SH-SY5Y细胞的氧化损伤，并诱导小胶质细胞向抗炎（M2）表型极化。体内研究进一步证明，Que@DAR NPs在大脑中动脉闭塞（MCAO）大鼠模型中抑制神经炎症，减少神经元凋亡，并显著改善神经功能障碍。总之，Que@DAR NPs为IS的精准治疗提供了一种安全有效的新策略。
