Glucose‐Triggered Gelation of Supramolecular Peptide Nanocoils with Glucose‐Binding Motifs

Abstract

Peptide self‐assembly is a powerful tool to prepare functional materials at the nanoscale. Often, the resulting materials have high aspect‐ratio, with intermolecular β‐sheet formation underlying 1D fibrillar structures. Inspired by dynamic structures in nature, peptide self‐assembly is increasingly moving toward stimuli‐responsive designs wherein assembled structures are formed, altered, or dissipated in response to a specific cue. Here, a peptide bearing a prosthetic glucose‐binding phenylboronic acid (PBA) is demonstrated to self‐assemble into an uncommon nanocoil morphology. These nanocoils arise from antiparallel β‐sheets, with molecules aligned parallel to the long axis of the coil. The binding of glucose to the PBA motif stabilizes and elongates the nanocoil, driving entanglement and gelation at physiological glucose levels. The glucose‐dependent gelation of these materials is then explored for the encapsulation and release of a therapeutic agent, glucagon, that corrects low blood glucose levels. Accordingly, the release of glucagon from the nanocoil hydrogels is inversely related to glucose level. When evaluated in a mouse model of severe acute hypoglycemia, glucagon delivered from glucose‐stabilized nanocoil hydrogels demonstrates increased protection compared to delivery of the agent alone or within a control nanocoil hydrogel that is not stabilized by glucose.

Glucose-Driven Droplet Formation in Complexes of a Supramolecular Peptide and Therapeutic Protein

“…The reduced electrostatic repulsion upon glucose binding would then be expected to enhance self-assembly and hydrogelation, as is also seen for other PA designs upon introduction of charge-screening ionic species or changes in pH. , As an alternative to a prior report exploring enzymatically driven hydrogelation in the presence of glucose through the actuation of xenogeneic glucose oxidase, the current approach envisioned with PA-PBA was thought to offer a more biocompatible and direct way to achieve a glucose-stabilized hydrogel for release of glucagon upon hypoglycemia. PBA-modified oligopeptides were previously shown to self-assemble into nanocoils that then became entangled into a hydrogel network upon PBA–glucose binding . However, initial efforts with the platform here failed to realize formation of a self-supporting hydrogel upon addition of glucose.…”

“…PBA-modified oligopeptides were previously shown to selfassemble into nanocoils that then became entangled into a hydrogel network upon PBA−glucose binding. 28 However, initial efforts with the platform here failed to realize formation of a self-supporting hydrogel upon addition of glucose. TEM of PA-PBA in its glucose-bound state instead revealed formation of spherical micellar structures (Figure S1), likely explaining the inability of this molecule to form the nanofibrillar hydrogels of a typical PA material.…”

“…The glucose-stabilized nature of these LLPS droplets was of interest to explore as a glucagon delivery technology in the context of hypoglycemia prevention. A previously established model in STZ-induced diabetic mice simulating prophylactic delivery prior to application of an insulin overdose was employed (Figure D). , Following a period of fasting and blood glucose normalization, droplets prepared in 100 mg/dL glucose-containing buffer were injected subcutaneously at a total dasiglucagon dose of 6 μg. Controls of buffer or dasiglucagon alone (6 μg) were also administered.…”

Strain-Stiffening Mechanoresponse in Dynamic-Covalent Cellulose Hydrogels

“…Hydrogels have high water content, porous structures, and are often biocompatible, which make these useful materials for many biologically relevant applications. − Mechanoresponsive hydrogels have been developed to undergo changes in their physical, chemical, and/or mechanical properties upon applied mechanical stimuli, including deformation, force, or pressure. , The engineering of mechanically responsive features can empower a variety of applications. For example, hydrogels exhibiting shear-thinning and self-healing have been engineered and are widely utilized as injectable vehicles for drug delivery and 3D printing. , Shear-thinning and self-healing behaviors are typically a result of dynamic-covalent bonds or noncovalent interactions, such as hydrogen bonding, metal–ligand coordination, host–guest interactions, and hydrophobic interactions. − These relatively weak interactions are disrupted at high shear rates or high strains but reform upon cessation of the mechanical stimulus, allowing for recovery of the initial hydrogel mechanical properties. Strain sensors have been designed using strain-stiffening poly­(acrylic acid)/poly­(acrylamide) hydrogels, which display a deviation from linear viscoelasticity when their stiffness increases upon the application of high strain. , Strain-stiffening oligo­(ethylene)­glycol polyisocyano-peptide hydrogels have also been used as synthetic extracellular matrices; the extent of their strain-stiffening in response to deformations by encapsulated mesenchymal stem cells impacted the differentiation of these cells toward osteogenesis or adipogenesis .…”