普通聚合物胶束的跨膜转运效能不尽如人意，对其胞内转运途径及分子调控机制的研究尚缺乏系统性和深度。本项目针对小肠特点，基于靶向策略提出有效提高胶束跨膜转运效能的新思路，拟构建寡肽转运体PEPT1的底物Phe-Gly修饰的PEG-PLA胶束。依据分子动力学模拟和竞争性抑制等确定的PLA-PEG-Phe-Gly与PEPT1的亲和性、稳定性和体外吸收等确定合适组成的PLA-PEG-Phe-Gly；根据胶束跨Caco-2细胞单层转运确定胶束中PLA-PEG-Phe-Gly的最佳含量；用先进的生物学方法，借助共聚焦显微镜观察胶束与细胞器的共定位，并用蛋白质组学联合LC/MS/MS确定胶束吸附的蛋白，阐明胶束的胞内转运途径；用siRNA下调/抑制胞内相关转运蛋白的表达，研究其对胶束跨膜转运之影响，从分子水平上揭示其胞内转运的机制。本研究将为构建低毒、高选择性和高跨膜转运效能的纳米载体提供理论依据和指导。

The transmembrane transport efficiency of plain polymeric micelles has been not satisfied, and the intracellular trafficking route and molecular regulation mechanism for polymeric micelles lacked of systematic and deep research. To this end, according to the characteristic of small intestine, the new idea has been developed to effectively enhance the transmembrane transport efficiency of polymeric micelles in the present research based on the targeting strategy. The Phe-Gly, the substrate of intestinal peptide transporter 1 (PETP1), modified polymeric micelles are to construct based on PEG-PLA. The appropriate composition of PLA-PEG-Phe-Gly is determined according to the affinity of PLA-PEG-Phe-Gly to PETP1 by calculation with molecular dynamics simulation and competitive inhibition test, the stability in intestine and in vitro absorption. The optimal content of PLA-PEG-Phe-Gly in micelles is determined by transmembrane transport of polymeric micelles across Caco-2 cell monolayer. Using advanced biological technologies and methods, the co-localizations of micelles with cell organelles are observed by using CLSM to elucidate the intracellular trafficking route for polymeric micelles, which is further clarified by the determination of the proteins adsorbed by micelles using proteomics methods in combination with LC/MS/MS. The expression of intracellular specific proteins is down-regulated or inhibited by using knockdown experiments with siRNAs. The molecular regulation mechanism of intracellular trafficking for polymeric micelles is revealed by investigation of the effect of the associated proteins on the transmembrane transport efficiency of polymeric micelles. The results of this research might provide the theoretical base and guidance for construction of nanocarriers with low toxic, highly selective and efficient transmembrane transport.