: The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has advanced diabetes management. Nevertheless, frequent administration remains a challenge, even with weekly formulations. Herein, we developed a sustained-release hydrogel-based delivery system for Efsubaglutide Alfa (Suba), an IgG-conjugated GLP-1RA, designed to alleviate treatment burden and enhance patient adherence.A series of biodegradable poly(lactic acid--glycolic acid)-poly(ethylene glycol)-poly(lactic acid--glycolic acid) (PLGA-PEG-PLGA) triblock copolymers were synthesized, and a thermosensitive PLGA-PEG-PLGA hydrogel with suitable sol-gel transition temperature anddegradation profile was selected for the fabrication of the Suba-loaded hydrogel system (Suba@T-gel). The pharmacokinetic and pharmacodynamic profiles following subcutaneous administration of Suba@T-gel were evaluated in multiple rodent models.non-invasive imaging and pharmacokinetic studies showed that a single subcutaneous injection of Suba@T-gel enabled sustained release of Suba for over three weeks. This prolonged release profile is attributed to moderate Suba-polymer interactions and the large molecular size of Suba, which facilitate sustained drug release through a carrier degradation-controlled mechanism. In diabetic murine models, a single administration of Suba@T-gel achieved stable glycemic control for three weeks. Furthermore, the continuous liberation of Suba remarkably enhanced insulin secretion, reduced glycosylated hemoglobin levels, and improved pancreatic function in diabetic mice. Additionally, this system ameliorated diabetes-related complications by improving lipid metabolism, reversing hepatic steatosis and enhancing nerve fiber density.The Suba@T-gel system represents a promising strategy for long-acting management of diabetes and substantial improvement in patient compliance. Rationale Methods: Results: Conclusions: co co in vivo In vivo
