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

## TL;DR

This study creates a genetic switch that uses a natural sweetener to control therapeutic protein production in mammals, offering a safer and more controllable cell-based therapy approach.

## Contribution

The PURE system uses a modified repressor to enable psicose-specific gene expression with low side effects in living organisms.

## Key findings

- The PURE system shows high sensitivity to low psicose concentrations and is insensitive to other sugars.
- Designer cells with the PURE system effectively lower blood glucose in diabetic mice and reduce body weight in obese mice.
- Psicose cola orally activates the system in vivo, demonstrating its practicality for therapeutic use.

## 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 psicose‐inducible transgene expression (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 (PsiRT135N;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.

This study develops a natural sweetener, the psicose‐inducible transgene expression (PURE) system based on an Agrobacterium tumefaciens–derived transcriptional repressor PsiR. The PURE system is highly specific to psicose, being insensitive to other sugars and structurally similar molecules. As a proof‐of‐concept, we demonstrate that microencapsulated designer cells can be activated by drinking psicose cola to regulate therapeutic protein expression in vivo, achieving glycaemic control in diabetic mice and body weight reduction in obese mice.