Peptide delivery in the management of diabetes : exploring bioinspired nanoarchitectures using stimuli-responsive materials and supramolecular depots

Abstract

Peptide therapeutics such as insulin and glucagon-like peptide-1 (GLP-1) analogues are central to diabetes management but remain constrained by rapid enzymatic degradation, poor epithelial permeability and short systemic half-life. Bioinspired nanoarchitectures have emerged as promising strategies to address these challenges by mimicking biological membranes, extracellular matrices and supramolecular peptide assemblies to enhance peptide stability, absorption and pharmacokinetic control. This review synthesised advances in membrane-mimetic lipid nanocarriers, polymer-based systems, peptide-driven self-assembling depots and stimuli-responsive nanoarchitectures. Lipid-inspired systems including hydrophobic ion-paired exenatide lipid nanocarriers achieved oral bioavailability of 16.3–27.9%. Comparably, polymer-based systems incorporating adaptive electrostatic or stimuli-responsive designs such as charge-switchable PCB122/INS nanoparticles coated capsules, enabled oral insulin bioavailability approaching ∼27%, translating into sustained glucose lowering effects in vivo. In addition, a polymeric D-PLA-PEG stereocomplex nanoassembly enabled ultra-long insulin release for up to 16 weeks following a single subcutaneous administration, maintaining controlled blood glucose levels in type 1 diabetic models. Peptide-driven supramolecular systems such as GLP-1 nanofibre hydrogels and cassette-assembled peptides demonstrated sustained glycaemic control lasting weeks to over 40 days in preclinical models. Interestingly, emerging glucose-responsive platforms including glucose oxidase-integrated hydrogels and ROS-responsive polymersomes, further enabled closed-loop insulin release with polymersomes releasing > 90% insulin under hyperglycaemic conditions. Importantly, several nanoarchitectures also supported cell-based therapies such as biomimetic pancreatic constructs combining stem-cell-derived islet cells with peptide-loaded nanomatrices to restore glycaemic regulation in type 1 diabetes models. Overall, these bioinspired platforms illustrate how nanomedicine can integrate barrier penetration, pharmacokinetic control and stimuli-responsive release to advance next-generation peptide delivery strategies for diabetes therapy.

HIGHLIGHTS • Bioinspired nanoarchitectures improve peptide stability and delivery. • Lipid and polymeric systems enhance oral peptide bioavailability. • Self-assembling depots enable sustained peptide release. • Glucose-responsive platforms provide on-demand insulin release. • Biomimetic nanomatrices support cell-based diabetes therapies.