A Natural Sweetener‐inducible Genetic Switch Controls Therapeutic Protein Expression in Mammals

ABSTRACT Cell‐based therapies are recognized as the next generation living therapeutics in medicine, especially through the design of synthetic gene switches to enhance the safety and controllability of engineered cells. However, current small molecule‐regulated synthetic gene switches face clinical limitations such as long‐term side effects and metabolic disturbances. Here, we develop a natural sweetener p sicose‐ind u cible t r ansgene e xpression (PURE) system based on the transcriptional repressor PsiR from Agrobacterium tumefaciens . We increase the induction sensitivity of PURE using computational docking to identify candidate PsiR mutations (PsiR _T135N;V134S ), thereby enhancing reporter expression in cell cultures exposed to low psicose concentrations. As a proof‐of‐concept, the designer cells equipped with the PURE system are encapsulated and implanted into the peritoneal cavity of type 1 diabetic (T1D) mice or high‐fat diet (HFD)‐induced obesity model mice. We show that the designer cells could regulate insulin expression to effectively lower blood glucose levels in T1D model mice and induce an anti‐obesity therapeutic protein (thymic stromal lymphopoietin, mTSLP) to reduce body weight in HFD mice, when the psicose‐containing soft drink (psicose cola) is orally administered. This study provides a practical and user‐friendly approach for sustained therapeutic protein delivery in next‐generation cell‐based therapies.