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 stimulidirected 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 highglucose 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.

Glucose-Responsive Injectable Thermogels via Dynamic-Covalent Cross-Linking of Pluronic Micelles

“…To evaluate the therapeutic function of insulin-loaded thermogels, male C57BL6/J mice (8 weeks, ∼25 g, Jackson Laboratory) were chemically induced with diabetes following a published protocol. 37 Mice were fasted for 4 h, following which a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 150 mg/kg) was administered.…”

Smart Hydrogels Bearing Transient Gel–Sol–Gel Transition Behavior Driven by a Biocompatible Chemical Fuel

“…1−8 One of the most important examples is the chemically fueled smart supramolecular hydrogels, which show enticing applications in the field of biomedicine. 9,10 Typically, the input of high-energy chemical fuel temporally converts the non-assembling precursors into gelators, which thereby selfassemble into hydrogels; however, once the chemical fuel is used out, the gelators will return to the original non-assembling state spontaneously, leading to a dynamic sol−gel−sol transition. 11−15 Along this line, various smart supramolecular hydrogels have been developed with the consumption of highenergy chemicals, such as methylating reagents, 16 1-(3dimethylaminopropyl)-(3-ethyl)carbonimide, 17−20 disulfide reducing agents, 11,21 and trichloroacetic acid (TCA).…”

Energy Landscapes of Supramolecular Peptide–Drug Conjugates Directed by Linker Selection and Drug Topology

“…It is increasingly appreciated that features such as molecular design, environmental conditions, and the rate and/or order of applied stimuli dictate the formation of both equilibrium and nonequilibrium states in supramolecular materials. − Accordingly, an underexplored facet of sPDCs is the complex free energy landscape and assembly pathways traversed to realize the final supramolecular materials; such considerations are likely to have implications for the functional use of these materials. Specifically, contributions of the drug moiety itself along with its mode of conjugation must be better explored to understand its role in dictating the thermodynamics of the final assembly.…”