Glucose-Fueled Peptide Assembly: Glucagon Delivery via Enzymatic Actuation

Abstract

Nature achieves remarkable function from the formation of transient, nonequilibrium materials realized through continuous energy input. The role of enzymes in catalyzing chemical transformations to drive such processes, often as part of stimuli-directed signaling, governs both material formation and lifetime. Inspired by the intricate nonequilibrium nanostructures of the living world, this work seeks to create transient materials in the presence of a consumable glucose stimulus under enzymatic control of glucose oxidase. Compared to traditional glucose-responsive materials, which typically engineer degradation to release insulin under high-glucose conditions, the transient nanofibrillar hydrogel materials here are stabilized in the presence of glucose but destabilized under conditions of limited glucose to release encapsulated glucagon. In the context of blood glucose control, glucagon offers a key antagonist to insulin in responding to hypoglycemia by signaling the release of glucose stored in tissues so as to restore normal blood glucose levels. Accordingly, these materials are evaluated in a prophylactic capacity in diabetic mice to release glucagon in response to a sudden drop in blood glucose brought on by an insulin overdose. Delivery of glucagon using glucose-fueled nanofibrillar hydrogels succeeds in limiting the onset and severity of hypoglycemia in mice. This general strategy points to a new paradigm in glucose-responsive materials, leveraging glucose as a stabilizing cue for responsive glucagon delivery in combating hypoglycemia. Moreover, compared to most fundamental reports achieving nonequilibrium and/or fueled classes of materials, the present work offers a rare functional example using a disease-relevant fuel to drive deployment of a therapeutic.