Work

On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system

Year: 2025

Type: article

Abstract: Here, we present StimExo as a rational design strategy allowing various user-defined control signals to trigger calcium-dependent exocytosis and mediate on-demand protein secretion in cell-therapy settings. Using a modular framework incorporating inducible protein-protein interactions into an engineered bipartite activator of calcium release–activated calcium (CRAC) channels, Ca2+ influx mediated by the STIM/Orai1 machinery was flexibly adjusted to depend on different user-defined input signals. Application of StimExo to various endocrine cells enables instant secretion of therapeutic hormones upon administration of safe and patient-compliant trigger compounds. StimExo also mediated insulin exocytosis using a cell-based gene delivery strategy in vivo, accounting for real-time control of blood glucose homeostasis in male diabetic mice in response to the FDA-approved drug grazoprevir. This study achieves true “sense-and-respond” cell-based therapies and provides a platform for remote control of in vivo transgene activities using various trigger signals of interest. On-demand drug secretion within patients is a long-standing goal of cell-based therapies. Here, the authors developed a trigger-inducible calcium importer to allow various trigger compounds of interest (e.g. FDA-approved drugs) to control exocytosis of insulin or other therapeutic proteins in vivo.

Source: Nature Communications

DOI: 10.1038/s41467-025-58184-9