Programmable Artificial Glucose-sensing Receptor for Autonomous Single-Cell Closed-loop Glycemic Control

Synthetic receptors enable programmable cellular functions, but their metabolism-regulating applications remain underexplored. Current synthetic cell strategies for glycemic control mimic pancreatic β-cell glucose-responsive insulin output to mediate peripheral glucose-uptake effector cells via multicellular closed-loop coordination, yet incurring delayed responses and limited efficacy under insulin resistance. Herein, we present a de novo-designed artificial glucose-sensing receptor (AGSR) enabling glucose-uptake effector cells (hepatocytes/myocytes) to sense glucose directly and achieve autonomous single-cell closed-loop glycemic regulation. AGSR is formed through equipping a cell-wearable glucose-regulating DNA nanodevice (CWGN) onto endogenous c-Met receptors, integrating glucose sensing, threshold-based decision-making, and c-Met-mediated metabolism-modulating actuation within a CWGN-built-in DNA molecular circuit. AGSR exhibits precise hyperglycemia-specific responsiveness, minute-level activation of glucose uptake, and sustained efficacy in insulin-resistant settings due to its insulin receptor-independence. In type 1 and type 2 diabetic mice/dog models, AGSR significantly improves glucose tolerance without hypoglycemia risk, highlighting the potential of DNA nanotechnology-based precision treatment of metabolic disorders.