本项目针对siRNA脑部传递中存在的主要问题，合成具有促内涵体逃逸功能、低毒性的载体聚合物-胆甾醇基修饰的聚乙二醇-b-聚（四亚乙基五胺）天冬氨酸提高转染效率，与BACE1干扰质粒孵育自组装构建可沉默β-分泌酶基因的聚离子复合物。而后将RDP肽和Tet1肽作为双重修饰配体，链接于聚离子复合物表面，构建一种双级脑靶向基因传递系统，增加脑部基因药物递送的选择性。分别考察优化聚合物的接枝度，靶向配体的修饰密度、复合物的N/P比等对系统的物化性能和生物学性能的影响。评价该传递系统细胞毒性，跨血脑屏障转运特性，细胞转染和基因沉默效率，初步考察细胞内转运机制和释放机制。并建立大鼠阿尔茨海默病模型，评价载药系统介导siRNA沉默BACE1基因以及对模型大鼠记忆和认知能力的提高。本研究为主动靶向、高效、低毒的非病毒基因载体构建及神经退行性疾病的基因治疗提供新的思路和必要的实验和理论依据。

In order to improve the efficiency of siRNA brain delivery and cell ransfection efficiency.A low toxicity copolymer PEG-P[Asp(TEP)]-cholesterol with endosomal escape function was synthesized.A novel polyion complex(PIC)is prepared by self-assemblely process in the presence of PEG-P[Asp(TEP)]-cholesterol and small interfering RNA plasmid specific for beta-secretase. The noval dual-brain targeting gene delivery system is constructed by using RDP combined with Tet1 peptide as the co-modification ligand and connecting to the surface of polyion complex(RDP/Tet1-PIC). We will investigate and optimize the degree of grafting of the polymer, the the density of the modified ligand on the surface of polyion complex, the compound of the N/P ratio of the polyion complex related to the physicochemical properties and biological properties of the gene delivery system. The brain transport property of the RDP/Tet1-PIC was evaluated, and the gene transfection efficiency of nerve cells and silencing efficiency of b-site amyloid precursor protein-cleaving enzyme1(BACE1) gene was investigated. initially the intracellular transport mechanism was investigated. Furthermore, RDP/Tet1-PIC loaded pGPU6/BACE1a improved the Amyloid-β25-35 induced learning and memory impairments in rats were investigated. After the establishment of the rat model of Alzheimer's disease, and the evaluation of RDP/Tet1-PIC loaded siRNA induce the BACE1 gene silencing in rat model. This study will have application prospects in the prevention and treatment of neurodegenerative diseases and provid a novel active targeting, high efficiency, low toxicity non-viral vectors and provide new ideas and the necessary experimental and theoretical basis.