ESPE Yearbook of Paediatric Endocrinology

Nat Nanotechnol. 2025 May;20(5):697-706. PMID: 40011600

Brief summary: A nuclear envelope–inspired membrane was developed to coat insulin crystals, enabling long-acting, self-regulated insulin delivery. The resulting i-crystal, featuring electro-responsive porous channels, allowed glucose- and ketone-triggered insulin release. With high drug-loading capacity and zero-order release kinetics, the i-crystal maintained blood glucose control for over one month in mice with type 1 diabetes (T1D).

Numerous efforts have been made to develop "smart insulin" systems that combine long-acting effects with responsiveness to ambient glucose and/or ketone levels. Various strategies have been explored, including glucose-binding polymers, glucose oxidase-based systems, and insulin analogs with glucose-sensitive modifications (1,2).

These investigators designed a nuclear envelope–inspired polymeric nano-membrane that is conformally synthesized around insulin crystals. This membrane integrates glucose- and ketones (β-hydroxybutyrate)-responsive microdomains and features nanopores that enable sustained, zero-order insulin release. Under hyperglycemia and ketonemia, these microdomains induced a negative membrane potential, triggering the expansion of nanopores and accelerating insulin release.

In preclinical models, this new insulin product demonstrated impressive performance: normoglycemia was maintained for over one month in T1D mice and up to three weeks in diabetic minipigs.

This innovative approach represents a major advancement in drug delivery technology. By combining zero-order release kinetics with metabolite-responsive control, it holds the potential to provide continuous, stable, and predictable insulin delivery. The ability to dynamically respond to fluctuations in glucose and ketone levels enhances its safety and efficacy, reducing the risk of both hypoglycemia and hyperglycemia. This work opens promising avenues for next-generation long-acting therapies for a better management of diabetes.

References: 1. Jarosinski MA, Dhayalan B, Rege N, Chatterjee D, Weiss MA. ’Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues. Diabetologia. 2021;64(5):1016-29.2. Hoeg-Jensen T, Kruse T, Brand CL, Sturis J, Fledelius C, Nielsen PK, et al. Glucose-sensitive insulin with attenuation of hypoglycaemia. Nature. 2024;634(8035):944-51.