Liu Yunsheng, Wang Xiaojun, Li Xiangzhu, Qiao Shanshan, Huang Guodong, Hermann Dirk Matthias, Doeppner Thorsten Roland, Zeng Muling, Liu Wei, Xu Gelin, Ren Lijie, Zhang Yuan, Liu Wenlan, Casals Eudald, Li Weiping, Wang Ya-Chao
Department of Neurosurgery, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, China.
Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
ACS Appl Mater Interfaces. 2021 Oct 6;13(39):46213-46224. doi: 10.1021/acsami.1c06449. Epub 2021 Sep 21.
Acute ischemic stroke has become the major cause of mortality and disability worldwide. Following ischemic stroke, the reperfusion injury is mainly mediated by the burst of reactive oxygen and nitrogen species (RONS). Therefore, blocking the excessive production or removing RONS holds great promise as a potential therapeutic strategy. Herein, we developed a Co-doped FeO nanozyme that is capable of scavenging HO, O, NO, and ONOO- in vitro and in vivo and provides neuroprotection against ischemic stroke. In vitro experiments showed that pre-incubation with the Co-FeO nanozyme could prevent neurotoxicity and neuroinflammation induced by HO or lipopolysaccharide, respectively, in HT22 cells. After intravenous administration, the Co-FeO nanozyme showed no signs of toxicity in peripheral organs of C57BL/6J mice, even after prolonged delivery for 4 weeks. In permanent photothrombotic stroke model and transient middle cerebral artery occlusion stroke model, the Co-FeO nanozyme specifically accumulated in the infarct rim at 72 h post-stroke and was endocytosed by neurons, astrocytes, microglia, and endothelial cells. Importantly, the Co-FeO nanozyme delivery reduced the infarct volume in both stroke models. The observation that the Co-FeO nanozyme was efficacious in two well-characterized ischemic stroke models provides strong evidence that it represents a powerful tool for targeting oxidative and nitrosative stress in the ischemic brain.
急性缺血性中风已成为全球范围内死亡和残疾的主要原因。缺血性中风后，再灌注损伤主要由活性氧和氮物种（RONS）的爆发介导。因此，阻断RONS的过量产生或清除RONS作为一种潜在的治疗策略具有很大的前景。在此，我们开发了一种共掺杂的FeO纳米酶，它能够在体外和体内清除HO、O、NO和ONOO-，并对缺血性中风提供神经保护作用。体外实验表明，用Co-FeO纳米酶预孵育可分别预防HT22细胞中由HO或脂多糖诱导的神经毒性和神经炎症。静脉给药后，即使在延长给药4周后，Co-FeO纳米酶在C57BL/6J小鼠的外周器官中也没有毒性迹象。在永久性光血栓性中风模型和短暂性大脑中动脉闭塞中风模型中，Co-FeO纳米酶在中风后72小时特异性地积聚在梗死边缘，并被神经元、星形胶质细胞、小胶质细胞和内皮细胞内吞。重要的是，Co-FeO纳米酶的递送减少了两种中风模型中的梗死体积。Co-FeO纳米酶在两种特征明确的缺血性中风模型中均有效的观察结果提供了有力证据，表明它是靶向缺血性脑氧化和亚硝化应激的有力工具。
