A Glucose-Responsive\nGlucagon-Micelle for the Prevention\nof Hypoglycemia

While glucose-responsive insulin delivery systems are\nin widespread\nclinical use to treat insulin insufficiency, the on-demand supplementation\nof glucagon for acute hypoglycemia treatment remains understudied.\nA self-regulated glucagon release material is highly desired to mitigate\nthe potential risks of severe insulin-induced hypoglycemia. Here,\nwe describe a glucose-responsive polymeric nanosystem with glucagon\ncovalently grafted to the end-group. Under normoglycemic conditions,\nphenylboronic acid units in the polymer chain reversibly bind glucose,\ntriggering self-assembly of the conjugate into micelles. During hypoglycemia,\nhowever, the micelle disassembles into its original, unimeric state,\nrevealing the active glucagon conjugate. The formulation showed a\n5-fold increase in activity compared to native glucagon when tested <i>in vitro</i>. Glucagon-loaded micelles injected into mice prevented\nor reversed deep hypoglycemia when administered prior to or during\nan insulin challenge. Glucagon release was only observed at or below\nthe counterregulatory threshold and not during normoglycemia or moderate\nhypoglycemia. The <i>in vivo</i> acute and chronic toxicity\nanalysis, along with μPET/μCT imaging, established the\nbiosafety profile of this formulation and demonstrated no organ accumulation.\nThis proof-of-concept work is the first step toward development of\na translational, stimuli-responsive glucagon delivery platform to\ncontrol glycemia.