Engineering Peptide Self-Assembly for Glucose-Responsive Glucagon Delivery

Stimuli-responsive materials are gaining traction in precise drug delivery, especially for diabetes management. Intensified insulin treatment can cause acute hypoglycemia (BGL < 70 mg/dL), leading to severe complications. Over 3 million severe hypoglycemic emergencies occur annually in the US. Administering exogenous glucagon during such episodes is critical, but impaired consciousness and nighttime occurrences hinder self-administration, particularly in children. Hence, an autonomous, smart glucagon delivery system is urgently needed. Stimuli-responsive materials enhance therapeutic efficacy by responding to analytes like pH, enzymes, glucose, and redox agents. Peptide self-assemblies are particularly effective due to their natural ability to form well-defined nanostructures and respond to specific stimuli for targeted drug delivery. Chapter 1 introduces disease-analyte-responsive peptide self-assemblies, focusing on design strategies for peptides that respond to cancer, inflammation, and diabetes-related analytes. It discusses leveraging peptide properties like hydrophobicity and secondary structure, emphasizing glucose-responsive materials. My research developed materials inspired by biological systems that exist in a non-equilibrium state, influenced by energy sources like ATP or GTP. Chapter 2 explores glucose oxidase (GOx) as a sensor to convert glucose signals into pH stimuli, driving pH-responsive peptide self-assembly into a hydrogel. This hydrogel encapsulates glucagon at normal glucose levels and releases it when glucose drops, marking a new paradigm in glucose-responsive material design. Despite challenges like GOx instability and cytotoxicity, this strategy showed promise. Chapters 3 and 4 investigate phenylboronic acid (PBA) as an alternative sensor. PBA forms stable boronated esters with glucose's cis-diols, acting as a switch in materials. Chapter 3 details a PBA-multidomain peptide (PBA-MDP) that forms a self-supporting hydrogel with rapid glucose-triggered responses, improving efficacy in mice. Chapter 4 explores peptide-based droplets, integrating PA-PBA with dasiglucagon for glucose-driven liquid-liquid phase separation (LLPS). These stabilized droplets proved effective in alleviating severe hypoglycemia in a mice model, offering a novel approach to glucagon delivery.