缺血性脑卒中是常见病、多发病、致残率高，迄今临床上少见疗效确切的治疗药物。我中心自主创新的nNOS-PSD-95解偶联剂ZL006能够显著抑制NMDAR-PSD-95-nNOS通路过度激活而释放的病理性NO，缩小脑梗死容积。然而，ZL006亲水性较强，难以透过血脑屏障（BBB），脑组织分布不理想。因此，为增强ZL006的脑靶向性，本项目采用BBB表面TfR特异性配体T7肽和脑缺血特异性归巢肽(SHp)双重修饰ZL006纳米脂质体，构建T7/SHp共修饰的双靶向ZL006脂质体递药系统。该系统在T7介导下透过BBB后，再在SHp特异性归巢作用下进一步浓集于缺血病灶，实现ZL006的脑内双重靶向递药。从而提高解偶联剂ZL006治疗效果并降低副作用，通过细胞水平及体内外实验，探讨该系统的双级靶向机制，为缺血性脑卒中靶向治疗研究提供一种全新的双重靶向策略和研究路径。本研究内容未见国内外相关报道。

Ischemic stroke is a common and frequently occurring disease with high disability rate. Hitherto, there is no effective drug of stroke treatment in clinic. An nNOS-PSD-95 uncoupler named ZL006 independently innovated in our research centre is able to significantly reduce the release of pathological NO through the inhibition of NMDAR-PSD-95-nNOS pathway over-activation, which reduces the infarct volume of brain. However, it is difficult for ZL006 to penetrate through the blood-brain barrier (BBB) because of it's strong hydrophilicity, reducing the distribution of ZL006 in brain tissue. Therefore, in order to enhance the brain targeting of ZL006, the transferrin receptor (TfR) specific ligand T7 peptide and specific stoke homing peptide (SHp) were used to doubly modify ZL006 nanoliposomes. The dual targeting ZL006 liposome delivery system built by T7/SHp modification could penetrate through BBB by T7-mediated transcytosis and further concentrate in the ischemic lesion by the specific homing ability of SHp, which enhanced the anti-ischemic stroke effect of ZL006 and reduced it's toxicity for the normal brain tissue. The two-stage targeting mechanisms of the dual targeting drug delivery system for stroke treatment will be investigated by in vitro and in vivo studies, which will provide a new dual targeting strategy and study experiences on ischemic stroke therapy research. There are no relevant reports of this study at home and abroad.