消化道上皮细胞屏障是药物纳米载体吸收最重要的生理屏障。药物纳米载体在上皮细胞内转运时面临“入胞容易跨细胞转运难”的科学问题；此外纳米载体的胞内命运不够清晰也严重制约了药物载体的合理设计。本课题基于上皮细胞囊泡定向转运的特殊生理机制（即囊泡能特异性识别、组装并定向转运具有特定信号的胞内物质），结合前期工作基础，拟设计一种仿生型高载药纳米晶。该纳米晶粒径小（<100nm），表面通过“笼状”结构的稳定剂修饰有特殊的信号序列，能高效入胞；入胞后通过特殊信号序列的介导，利用囊泡的转胞吞作用从上皮细胞基底侧胞吐，实现高效跨细胞转运，达到促吸收的目的。本课题采用超分辨率STED显微镜，粒子追踪，全内反射荧光显微镜等技术对转运机制进行系统深入研究，希望为难吸收药物口服纳米载体的合理设计提供依据。

The intestinal epithelium remains a great barrier for oral drug delivery using nanocarriers. The transport of nanocarriers in epithelial cells faces a challenge of "easy entry and hard across", and their intracellular fate is still unclear, therefore significantly restricting the rational design of nanocarrier system for efficient oral drug delivery. This project is proposed based on the mechanism of vesicle transport (i.e. the transport vesicle in cells can specifically recognize, assemble and directionally transport endogenous materials with specific signs) and our previous findings, aiming to design a bio-inspired nanocrystals. This nanocrystals have a very small particle size (below 100 nm), and a functional signal sequence which is bonded to “nanocage” stabilizer via covalent conjugation. This bio-inspired nanocrystals can be significantly endocytosed by intestinal cells, then transport across epithelial cells via transcytosis hijacking transport vesicles, therefore, the transport of drug across intestinal epithelium can be greatly improved, and improving oral absorption. The deep understandings on the mechanism of drug transport across epithelium will be gained by STED super-resolution microscopy, real-time particle tracking , total internal reflection fluorescence microscopy techniques. etc. The findings of this project will dramatically advance our understanding on detailed dynamic trafficking of nanocarriers in cells, and provide solid principles for the rational design of nanocarrier system for oral drug delivery.