消化道环境、肠上皮细胞及其分泌的粘液层是蛋白多肽口服吸收的主要障碍及导致其生物利用度低的重要原因。目前的口服给药系统对于同时克服以上多重屏障缺乏有效手段。本项目受某些病毒能自由穿过粘液层启发，构建载胰岛素仿病毒纳米粒。该纳米粒选用介孔二氧化硅为纳米载体，其表面修饰-COOH后可获得其它材料无法达到的低负电势（低于-60 mV）。接着在其表面修饰带正电的细胞穿膜肽TAT，形成表面高密度带等量正负电荷的载胰岛素仿病毒纳米粒。纳米粒表面因包覆高密度电荷呈现亲水性、正负电荷等量排布使表面呈电中性，避免了与负电和疏水性粘液层发生静电或疏水作用，从而顺利穿过粘液层，达到上皮细胞附近。然后通过表面TAT介导上皮细胞摄取，达到克服消化道环境、肠上皮细胞及粘液层多重屏障，促进药物吸收的目的。本项目首次采用介孔二氧化硅为纳米载体达到促进粘液穿透、上皮细胞摄取的目的，为蛋白多肽类药物口服吸收提供了全新的策略。

Harsh intestine environment, epithelium and mucus layer covering the epithelium contribute significantly to the extremely low bioavailability of protein and peptide therapeutics administered orally. Nevertheless, many viruses are capable of diffusing in mucus as fast as in water. These viruses are densely coated with both positively and negatively charged groups, leading to a densely charged yet net neutral surface. We aim to design a nanoparticle with similar surface as that of these viruses to facilitate mucus penetrating and cell uptake. The nanoparticles are prepared by modification of mesoporous silica nanoparticles (MSN) with densely charged carboxylic groups and further with a cationic cell penetrating peptide TAT. The attachment of TAT neutralizes the negative charges conveyed by the carboxylic groups so as to obtain an electrically neutral MSN with an electrically neutral and hydrophilic surface densely but equally covered with both positive and negative charges. The MSNs so obtained avoid both electrical and hydrophobic interactions with the mucus layer so as to diffuse easily within the mucus layer to reach the epithelium layer. The TAT attached on the surface of the MSNs then mediate the endocytosis of the nanoparticle into and across the epithelium to reach the blood capillary beneath the epithelium layer. The loaded model drug, insulin, is then released and enters, alone or with the nanoparticle, into the circulation. The proposed neutrally charged MSNs overcome the multiple barriers simultaneously in order to orally deliver protein and peptide drugs such as insulin, hopefully offering a new strategy for design of oral delivery system for protein and peptide therapeutics.