A contractile DNA ligand restores insulin responsiveness by reorganizing the insulin receptor
Insulin resistance is commonly treated by increasing insulin exposure or amplifying downstream pathways, but these approaches do not directly repair the receptor-level defects that limit cellular responsiveness. Here we show that insulin resistance can be intervened by resetting the spatial state of the insulin receptor itself. We developed a programmable DNA biomimetic ligand that binds insulin receptors and undergoes insulin triggered contraction through an integrated sensing module. Rather than acting as an exogenous agonist, this system uses insulin as the signal that drives nanoscale shortening between neighboring receptor monomers, thereby restoring receptor clustering, autophosphorylation, and AKT activation in insulin resistant hepatocytes. Recovered receptor responsiveness enhances glucose uptake, rebalances glycolytic and lipogenic gene expression, and reduces intracellular lipid accumulation. In high-fat-diet-induced mice, systemic administration improves glucose tolerance and insulin sensitivity, lowers circulating triglycerides and cholesterol, and alleviates hepatic steatosis without evident toxicity. Rather than replacing insulin signaling, this approach restores the ability of cells to read physiological insulin by reorganizing the receptor at the cell surface.