Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.

胰岛素的口服制剂通常旨在改善其肠道吸收并增加其血液生物利用度。在这里，我们展示了从一组胆汁酸聚合物中选出并配制成用于口服胰岛素的纳米颗粒的聚合熊去氧胆酸可以恢复患有 1 型糖尿病的小鼠和猪的血糖水平。纳米颗粒作为保护性胰岛素载体和高亲和力胆汁酸受体激动剂发挥作用，增加胰岛素的肠道吸收，使肠道巨噬细胞极化为 M2 表型，并优先在小鼠胰腺中积累，与胰岛结合-细胞胆汁酸膜受体 TGR5，具有高亲和力并激活胰高血糖素样肽和内源性胰岛素的分泌。在小鼠中，纳米粒子还可以逆转炎症、恢复代谢功能并延长动物的生存期。当封装雷帕霉素时，它们延迟了化学诱导的胰腺炎症小鼠患糖尿病的时间。可摄入胆汁酸聚合物纳米载体的代谢和免疫调节功能可能为预防和治疗 1 型糖尿病提供转化机会。