Title : Glucose-responsive smart polymeric nanocarriers for oral insulin delivery: Design, optimization, and preclinical evaluation
Abstract:
Background: Oral insulin delivery remains a long-standing challenge due to enzymatic degradation and poor intestinal permeability. Glucose-responsive smart polymeric nanocarriers represent an emerging strategy to enable self-regulated insulin release while improving bioavailability. This study aimed to develop and optimize a phenylboronic acid-functionalized polymeric nanoparticle system for glucose-triggered oral insulin delivery.
Methods: Insulin-loaded glucose-responsive nanoparticles (GR-NPs) were fabricated using a modified double-emulsion solvent evaporation method. A Box–Behnken experimental design was applied to optimize polymer ratio, crosslinking density, and surfactant concentration. Particle size, PDI, zeta potential, encapsulation efficiency, and in vitro glucose-triggered release were evaluated. Protection against simulated gastric and intestinal fluids was assessed. Caco-2 permeability studies and in vivo hypoglycemic efficacy were investigated in streptozotocin-induced diabetic rat models.
Results: Optimized GR-NPs exhibited a mean diameter of 168 ± 9 nm, PDI 0.19, and zeta potential of −14 mV. Encapsulation efficiency reached 81.6%. The nanoparticles demonstrated minimal insulin release (<12%) under normoglycemic conditions (5 mM glucose) but showed significantly enhanced release (68% over 6 h) under hyperglycemic conditions (20 mM glucose). In simulated gastric fluid, insulin degradation was reduced by 74% compared to free insulin. Apparent permeability (Papp) across Caco-2 monolayers increased 3.1-fold. In vivo studies showed a sustained hypoglycemic effect for up to 14 hours with a relative bioavailability of 18.4%, compared to subcutaneous insulin.
Conclusion: The developed glucose-responsive nanocarrier system demonstrates promising potential for self-regulated oral insulin delivery, improving stability, permeability, and therapeutic efficacy. This platform may represent a significant step toward non-invasive diabetes management and scalable smart oral biologics.
Keywords: Oral Insulin, Glucose-Responsive Nanoparticles, Smart Drug Delivery, Phenylboronic Acid, Polymeric Nanocarriers, Diabetes Therapy
