粘液层对纳米载体的快速捕捉和清除，已成为其促药物口服吸收的主要限制之一。虽然表面亲水性的纳米载体粘液穿透能力强，但在上皮细胞表面滞留时间短，且进入细胞能力显著降低，难以充分发挥递药作用。穿透粘液扩散屏障和上皮细胞吸收屏障所需纳米载体表面性质截然不同。常规口服纳米载体无法解决这一矛盾。本项目利用空肠上皮细胞表面与粘液间酸性微环境特性，构建了表面亲/疏水性、带电性和粘附性智能转变的多功能纳米粒。该纳米粒可在酸敏感的PEG外壳掩饰下快速穿透粘液层，到达上皮细胞后在其表面酸性微环境下，智能响应脱落PEG，暴露正电性壳寡糖纳米粒，粘附在上皮细胞表面并通过内吞或打开细胞旁路促药物高效吸收入血。以胰岛素为模型药物，研究多功能纳米粒穿透粘液层、继而酸敏感脱去PEG外壳和跨上皮细胞吸收的能力及机制；大鼠体内药动学及糖尿病模型大鼠的药效学。该策略为克服常规纳米载体固定表面性质存在的递药瓶颈问题提供了新的思路。

The rapid capture and clearance of nanocarriers by the mucus layer has become one of the major limitations of oral drug absorption. Although nanocarriers with hydrophobic surface have high mucus-penetrating ability, but their retention time in the epithelial cell surface is short, and the ability to enter the cell is significantly reduced, resulting in unefficient drug absorption improvement. The surface properties of the nanocarriers required to penetrate the mucus diffusion barrier and the epithelial cell absorption barrier are distinctly different. Conventional oral nanocarriers can not solve this contradiction. In this project, multifunctional nanoparticles with smart transformation of surface hydrophilicity/ hydrophobicity, electrification and adhesion would be constructed based on the acidic microenvironment between the surface of jejunum epithelial cells and the mucus. The nanoparticles can penetrate the mucus layer quickly through masking of an acid-sensitive PEG shell. When reach the acidic microenvironment in the surface of the epithelial cells, the PEG shell would shed from the nanoparticles. The positively charged chitooligosaccharides nanoparticles would adhere to the epithelial cells and improve drug absorption through endocytosis or opening the cell bypass. The ability and mechanism of multi-functional nanoparticles to penetrate the mucus layer, acid-sensitive PEG-shell shedding and epithelial cell uptake would be studied. The pharmacokinetics of the nanoparticles as well as its therapeutic effect in the diabetic rats would be also studied. This strategy will provide a new idea to overcome the bottleneck problem of conventional nanocarriers with constant surface properties.