缺血性脑卒中是一种严重危害人类健康的脑部疾病，我中心自主创新的神经保护剂ZL006与溶栓剂tPA协同用药是极具潜力的治疗方案。然而，两药合用时存在tPA循环时间短，血栓靶向性弱，溶栓时间窗窄、ZL006脑组织渗透差及二者体内时空选择控制性差等问题。本项目在前期研究基础上，从共递送载体出发，利用血栓部位高表达Thrombin和缺血脑组织酸性pH为智能释药“开关”，以载ZL006的pH敏感聚合物纳米粒为核，可被Thrombin酶切释放并串联Tat肽的tPA接枝血小板膜为壳，构建程序化响应释药的“核-壳”型血小板膜仿生共递送载体。该载体先靶向脑血栓，在血栓处响应性释放tPA溶解血栓，随后“原位暴露”的Tat介导载体透过BBB进入缺血脑组织，pH响应下释放ZL006。达到了长循环、血栓靶向、脑靶向及两药体内时空选择性释药的tPA/ZL006共递送，开辟了全新的缺血性脑卒中药物共递送载体构建策略。

Ischemic stroke is a serious brain diseases that threaten human beings. It is potential to treat ischemic stroke by combination thrombolytic agents tPA and neuroprotective agents ZL006 which was created innovatively in our research centre. However, the present shortcomings of the combination therapy include the short half time, weak targeting capacity to thrombus and narrow thrombolytic time window of tPA, as well as the poor penetration into brain of ZL006 and poor controllability of temporal and spatial selectivity in vivo. In this research project, we study the solving strategy from the point of drug delivery system based on our preliminary studies. Herein, we use the thrombin up-regulated in thrombus and low pH microenvironment in ischemic brain tissue as smart "switch" of drug release to develop a "core - shell" co-delivery carrier of ZL006 and tPA. The mutifunctional nanocarrier has a core of ZL006 loaded pH-sensitive polymer nanoparticles and a outer shell of platelet membrane that grafted by tPA via thrombin cleavage amino acid sequence conjugated with Tat peptides. The programmed and responsive platelet biomimetic delivery system will target to thrombus and release tPA by thrombin cleaved, which in situ exposed the Tat peptides outside of the carrier that mediates the remain carrier penetrate BBB into the brain. Then, the ZL006 will be released rapidly from the carrier disassembled in the acid microenvironment of ischemic brain tissue. The co-delivery system developed in this project will prolong the tPA's half time and enhance its thrombus targeting ability as well as improve the BBB penetration of ZL006 by "in-situ exposure" of Tat peptides, which satisfied the request of in vivo temporal and spatial selectivity of tPA/ZL006 release for stroke treatment. Our proposal will provide a novel co-delivery strategy for the drug delivery system study of ischemic stroke.