A series of semaglutide-loaded sustained-release formulations is developed using thermosensitive hydrogel as the release system. Micro-needle jet injection (MNJI) devices are used to deliver the highly viscous material and achieve a desired dispersion at delivery. Physicochemical properties, in vitro drug release behavior, and biocompatibility are systematically characterized. Therapeutic efficacy is evaluated in DIO rats, with non-sustained formulation as control to assess efficacy and sustainability. P407-based hydrogel has temperature-dependent sol-gel transition: at low temperature it is injectable, while at body temperature it becomes a solid gel to restrict semaglutide release. Drug incorporation did not interfere with this property. MNJI devices effectively delivered the formulation with consistency and showed favorable safety without severe inflammation. The system prolonged half-life to 15 h, extended Tmax from 8 to 24 h, and maintained effective levels to day 6. In DIO rats, GT10 50 achieved continuous weight loss over 20 days, overcoming the plateau of non-sustained formulations. Serum assays revealed significant reductions in TC (p < 0.01), ALT (p < 0.05), and AST (p < 0.01), indicating improved dyslipidemia and liver injury. Glucose tolerance tests confirmed alleviation of hyperglycemia without hypoglycemia. This study provides a strategy for obesity management with good efficacy and improved compliance via reduced dosing.
