Glucose-responsive formulations of insulin can increase its therapeutic index and reduce the burden of its administration. However, it has been difficult to develop single-dosage formulations that can release insulin in both a sustained and glucose-responsive manner. Here we report the development of a subcutaneously injected glucose-responsive formulation that nearly does not trigger the formation of a fibrous capsule and that leads to week-long normoglycaemia and negligible hypoglycaemia in mice and minipigs with type 1 diabetes. The formulation consists of gluconic acid-modified recombinant human insulin binding tightly to poly-l-lysine modified by 4-carboxy-3-fluorophenylboronic acid via glucose-responsive phenylboronic acid–diol complexation and electrostatic attraction. When the insulin complex is exposed to high glucose concentrations, the phenylboronic acid moieties of the polymers bind rapidly to glucose, breaking the complexation and reducing the polymers’ positive charge density, which promotes the release of insulin. The therapeutic performance of this long-acting single-dose formulation supports its further evaluation and clinical translational studies.

胰岛素的葡萄糖反应性制剂可以提高其治疗指数并减轻其给药负担。然而，开发能够以持续且葡萄糖响应的方式释放胰岛素的单剂量制剂一直很困难。在这里，我们报告了一种皮下注射葡萄糖反应制剂的开发，该制剂几乎不会触发纤维囊的形成，并且可以在患有 1 型糖尿病的小鼠和小型猪中导致为期一周的正常血糖和可忽略不计的低血糖。该制剂由葡萄糖酸修饰的重组人胰岛素组成，通过葡萄糖响应性苯基硼酸-二醇络合和静电吸引，与 4-羧基-3-氟苯基硼酸修饰的聚-L-赖氨酸紧密结合。当胰岛素复合物暴露于高葡萄糖浓度时，聚合物的苯基硼酸部分快速与葡萄糖结合，破坏复合物并降低聚合物的正电荷密度，从而促进胰岛素的释放。这种长效单剂量制剂的治疗性能支持其进一步评估和临床转化研究。