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Glucose-responsive hydrogel systems are increasingly explored for insulin delivery, with dynamic-covalent crosslinking interactions between phenylboronic acids (PBA) and diols forming a key glucose-sensing mechanism. However, commonly used PBA and diol chemistries often have limited responsiveness to glucose under physiological concentrations. This is due, in part, to the binding of PBA to the commonly used diol chemistries having higher affinity than for PBA to glucose. The present study addresses this challenge by redesigning the diol chemistry in an effort to reduce its binding affinity to PBA, thereby enhancing the ability of glucose to compete with these redesigned PBA–diol crosslinks at its physiological concentration, thus improving responsiveness of the hydrogel network. Rheological analyses support enhanced sensitivity of these PBA–diol networks to glucose, while insulin release likewise improves from networks with reduced crosslink affinities. This work thus offers a new molecular design approach to improve glucose-responsive hydrogels for insulin delivery in diabetes management.
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This content will become publicly available on January 1, 2026
Supramolecular Peptide Depots for Glucose‐Responsive Glucagon Delivery
This study investigates the development of a supramolecular peptide amphiphile (PA) material functionalized with phenylboronic acid (PBA) for glucose-responsive glucagon delivery. The PA-PBA system self-assembles into nanofibrillar hydrogels in the presence of physiological glucose levels, resulting in stable hydrogels capable of releasing glucagon under hypoglycemic conditions. Glucose responsiveness is driven by reversible binding between PBA and glucose, which modulates the electrostatic interactions necessary for hydrogel formation and dissolution. Through comprehensive in vitro characterization, including circular dichroism, zeta potential measurements, and rheological assessments, the PA-PBA system is found to exhibit glucose-dependent assembly, enabling controlled glucagon release that is inversely related to glucose concentration. Glucagon release is accelerated under low glucose conditions, simulating a hypoglycemic state, with a reduced rate seen at higher glucose levels. Evaluation of the platform in vivo using a type 1 diabetic mouse model demonstrates efficacy in protecting against insulin-induced hypoglycemia by restoring blood glucose levels following an insulin overdose. The ability to tailor glucagon release in response to fluctuating glucose concentrations underscores the potential of this platform for improving glycemic control. These findings suggest that glucose-stabilized supramolecular peptide hydrogels hold significant promise for responsive drug delivery applications, offering an approach to manage glucose levels in diabetes and other metabolic disorders.
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- Award ID(s):
- 1944875
- PAR ID:
- 10577914
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Journal of Biomedical Materials Research Part A
- Volume:
- 113
- Issue:
- 1
- ISSN:
- 1549-3296
- Page Range / eLocation ID:
- e37854
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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