Oral delivery of protein drugs is considered a life-changing solution for patients who require regular needle injections. However, clinical translation of oral protein formulations has been hampered by inefficient penetration of drugs through the intestinal mucus and epithelial cell layer, leading to low absorption and bioavailability, and safety concerns owing to tight junction openings. Here we report a zwitterionic micelle platform featuring a virus-mimetic zwitterionic surface, a betaine side chain and an ultralow critical micelle concentration, enabling drug penetration through the mucus and efficient transporter-mediated epithelial absorption without the need for tight junction opening. This micelle platform was used to fabricate a prototype oral insulin formulation by encapsulating a freeze-dried powder of zwitterionic micelle insulin into an enteric-coated capsule. The biocompatible oral insulin formulation shows a high oral bioavailability of >40%, offers the possibility to fine tune insulin acting profiles and provides long-term safety, enabling the oral delivery of protein drugs.

对于需要定期针头注射的患者来说，口服蛋白质药物被认为是一种改变生活的解决方案。然而，口服蛋白质制剂的临床转化受到药物通过肠粘液和上皮细胞层的低效渗透的阻碍，导致吸收和生物利用度低，以及由于连接开口紧密而引起的安全问题。在这里，我们报告了一种两性离子胶束平台，该平台具有模拟病毒的两性离子表面、甜菜碱侧链和超低临界胶束浓度，使药物能够通过粘液渗透和有效的转运蛋白介导的上皮吸收，而无需紧密连接开口。该胶束平台用于通过将两性离子胶束胰岛素的冻干粉末封装到肠溶包衣胶囊中来制造原型口服胰岛素制剂。生物相容的口服胰岛素制剂显示出 > 40% 的高口服生物利用度，提供了微调胰岛素作用曲线的可能性并提供长期安全性，从而能够口服递送蛋白质药物。