Glucose-responsive probiotics for glycaemic modulation in mice and monkeys.
Sustained and controlled delivery of glucose-lowering agents using engineered designer cells is recognized as an effective strategy for diabetes therapy1. However, current technologies rely on external signal control or have been programmed into mammalian cells using synthetic gene networks, which pose safety concerns arising from transplantation2,3. Here we developed an engineered oral-deliverable glucose-sensing and functional response probiotic living drug for 'sense-and-respond'-based control of diabetic blood glucose. We created a glucose sensor based on a synthetic gene circuit that incorporates the glucose-responsive transcriptional regulator HexR, coupled with a synthetic promoter. Upon oral administration of the engineered probiotics carrying the sensor, the cells reside temporarily in the intestine and regulate the expression of therapeutic transgenes in response to glucose levels that exceed the normal threshold. We show efficacy from the engineered probiotics for glycaemic control in multiple diabetic mouse and non-human primate models, demonstrating that long-term oral administration drives clear improvements in lipid profiles, while also attenuating development of multiple diabetic complications. Our probiotics-based living drug enables therapeutic dosing in response to real-time blood glucose levels, providing a programmable, orally deliverable sense-and-respond platform for metabolic therapy without transplantation.