真黑素样抗氧化-抗炎症纳米体系协同诊疗急性缺血性脑卒中的实验研究

Molecular cascade events caused by inflammatory reaction and oxidative stress induced by overproduced reactive oxygen and nitrogen species are core pathological nodes in acute ischemic stroke (AIS), which are closely associated with ischemia-reperfusion injuries. The blood-brain barrier hampers most therapeutic agents from entering the intracranial region. The project fabricates manganese-eumelanin nanocomposites with desirable water dispersibility via intra-polymerization doping strategy, as antioxidant and anti-inflammatory functional components and nano-carriers, with epidermal growth factor-like domain-1 as target module and curcumin as neuroprotective agent, respectively, to construct multifunctional nanocomposites EPMC. Based on middle cerebral artery occlusion induced focal ischemic brain injury mouse model, EMPC are efficiently delivered to the ischemic area mediated by the hypercoagulability of the ischemic area and the blood-brain barrier penetrating capacity of nanosystem. The EGF1 mediated enhancement features of T1-T2 magnetic resonance imaging and photoacoustic imaging are analyzed to accurately identify the location of cerebral vascular injury. The performance of EPMC on ischemia-reperfusion injury inhibition, and AIS nerve function and prognosis improvement are evaluated. EPMC is composed of natural components and owns excellent biocompatibility and biodegradability and thus good clinical translation potential. This project will provide innovative avenues for constructing multi-functional theranostic nanosystems with high safety and high performance against AIS.

活性氧和活性氮簇积聚所致的氧化应激和炎症反应引起的分子级联事件是急性缺血性脑卒中(AIS)的核心病理环节，与缺血再灌注损伤密切相关。血脑屏障的阻碍导致大多数治疗制剂难以进入脑内发挥疗效。项目拟通过聚合内掺杂策略一步合成具有良好水分散性的锰-真黑素样纳米配合物，作为抗氧化-抗炎症功能组分和纳米载体，表皮生长因子样结构域-1为靶向模块，姜黄素为神经保护剂，构建多功能纳米复合物EPMC。采用小鼠大脑中动脉闭塞所致局灶性缺血性脑损伤模型，利用缺血区域高凝状态及纳米体系可穿透血脑屏障的特性，观测EGF1靶向介导的T1-T2磁共振和光声成像强化特征，准确识别脑血管受损病灶；评价EPMC抑制缺血再灌注损伤、改善AIS神经功能及预后的效果，明确EPMC发挥作用的可能机制。EPMC由天然组分构成，具有优异的生物相容性和生物可降解性，临床转化前景良好。项目将为构建安全高效的AIS多功能纳米诊疗体系提供新途径。

活性氧和活性氮积聚所致的氧化应激和炎症反应引起的分子级联事件是多种中枢神经系统疾病的核心病理环节，与不良预后密切相关。然而，血脑屏障的阻碍导致大多数治疗制剂难以进入颅内病灶区域发挥疗效。随着纳米医学的快速发展，类黑色素仿生纳米材料作为一种极具潜力的抗氧化-抗炎症多功能纳米制剂受到了广泛的关注，在抵抗氧化应激中展现出独特的优势。在本项目的资助下，我们探索了多功能类黑色素纳米复合物的制备及其用于急性缺血性卒中和创伤性脑损伤靶向诊疗的可行性和有效性，并探索了其发挥作用的可能机制。我们发现：（1）采用狂犬病病毒肽RVG过表达的工程化细胞膜包裹类黑色素纳米颗粒，获得的纳米复合物nDOP-RVG能够在急性缺血性卒中模型小鼠的颅内病灶区域高效富集，逆转缺血再灌注导致的神经功能损伤。这涉及抑制神经细胞凋亡、修复血脑屏障、减轻神经炎症、修复线粒体功能损伤等多种机制的共同作用；（2）采用angiopep-2肽对锰掺杂的类黑色素纳米颗粒进行功能化修饰，并装载神经保护剂姜黄素，获得的纳米复合物ANG-MnEMNPs-Cur能够在创伤性脑损伤模型小鼠的颅内病灶区域高效富集，通过减轻氧化应激和诱导巨噬细胞重编程实现抑制神经炎症和促进神经元再生，从而实现满意的治疗效能。总之，项目验证了类黑色素纳米材料用于氧化应激相关疾病诊疗的可行性和有效性，将为开发基于黑色素的仿生功能纳米诊疗体系提供新思路。.项目的各项研究工作围绕申请书内容开展和扩展，取得了较好结果，实现了预期目标。在本项目的资助下，项目负责人发表SCI论文8篇，英文学术专著1章，并有其他多项研究成果正在陆续整理发表中。