Dual-phase exenatide delivery system: PLGA nanoparticles embedded in thermosensitive PLGA-PEG-PLGA hydrogel for sustained glycemic control

Glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated significant clinical efficacy in recent years for the treatment of type 2 diabetes mellitus (T2DM) and obesity. However, their widespread application remains constrained by limitations such as low oral bioavailability and poor patient compliance due to frequent injections. This study developed a biphasic delivery system (Ex-NPs-gel) integrating poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA) thermosensitive hydrogel with nanoparticles (NPs) for sustained-release injectable formulations. Exenatide-loaded nanoparticles (Ex-NPs) were prepared via the double emulsion solvent evaporation method and encapsulated into PLGA-PEG-PLGA hydrogel. The prepared NPs and hydrogel composite were subsequently evaluated for their physicochemical properties and in vitro/in vivo performance. In vitro studies demonstrated that Ex-NPs-gel achieved sustained exenatide release over 31 days with an initial burst release below 9% within the first 24 hours. In T2DM rat models, a single administration induced fasting blood glucose stabilization for over 15 days and restored hepatic/pancreatic functions. This system overcomes technical bottlenecks of conventional PLGA carriers and single-phase gels through modulation of release kinetics, offering a biocompatible and clinically translatable solution for long-acting polypeptide delivery.