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Virus-Mimicking Mesoporous Silica Nanoparticles with an Electrically Neutral and Hydrophilic Surface to Improve the Oral Absorption of Insulin by Breaking Through Dual Barriers of the Mucus Layer and the Intestinal Epithelium

Yi Zhang,Mengting Xiong,Xiaomin Ni,Jingrou Wang,Hehui Rong,Yuqing Su,Shihui Yu,Imran Shair Mohammad,Sharon Shui Yee Leung,Haiyan Hu

Protein and peptide drugs orally suffer from extremely low bioavailability principally for the complicated gastrointestinal environment along with the difficulty of passing through the mucus layer and the underlying epithelium. In our work, we fabricated mesoporous silica nanoparticles with modification groups (MSN-NH2@COOH/CPP5) that effectively penetrated the mucus layer and passed through the intestinal epithelium by mimicking the virus surface. Naked nanoparticles were prepared with inner pores of 6 nm diameter to allow efficient insulin loading and coated with the cationic cell-penetrating KLPVM peptide and the anionic glutaric anhydride to yield hydrophilic MSN-NH2@COOH/CPP5 with a ζ-potential of −0.49 mV. The apparent permeability coefficient of virus-mimicking nanoparticles was 14.61 × 10–5 cm/s. The virus-mimicking nanoparticles showed dramatically lower binding to mucin and faster penetration of the mucus layer than positively charged nanoparticles (MSN@NH2) with a ζ-potential of +35.00 mV. The KLPVM peptide enhanced the uptake of MSN-NH2@COOH/CPP5 by coculturing Caco-2 and E12 cells as an intestinal epithelium model. MSN-NH2@COOH/CPP5 enhanced apical-to-basal transcytosis for being internalized primarily through caveolae-mediated endocytosis. Indeed, for MSN-NH2@COOH/CPP5, the transepithelial transport of the Caco-2 cell monolayer was 2.4-fold higher than MSN@NH2 and 2.0-fold higher than MSN-NH2@COOH. In vitro, loading insulin into nanoparticles maintained the bioactivity of the protein under simulated intestinal conditions. Insulin loaded into MSN-NH2@COOH/CPP5 reduced the diabetic rats’ blood glucose level by nearly 50%. The bioavailability of insulin encapsulated in the MSN-NH2@COOH/CPP5 nanoparticles was 2.1-fold more than insulin when administered directly into the jejunum. Nanoparticles with modifications indicated no significant toxicity in in vitro or in vivo preliminary studies. The obstacles of the mucus layer and intestinal epithelium may be effectively conquered by these virus-mimicking nanoparticles for oral delivery of protein and peptide drugs.