pH‐temperature Responsive Hydrogel‐Mediated Delivery of Exendin‐4 Encapsulated Chitosan Nanospheres for Sustained Therapeutic Efficacy in Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2D) is a chronic, obesity‐related, and inflammatory disorder characterize by insulin resistance, inadequate insulin secretion, hyperglycemia, and excessive glucagon secretion. Exendin‐4 (EX), a clinically established antidiabetic medication that acts as a glucagon‐like peptide‐1 receptor agonist, is effective in lowering glucose levels and stimulating insulin secretion while significantly reducing hunger. However, the requirement for multiple daily injections due to EX's short half‐life is a significant limitation in its clinical application, leading to high treatment costs and patient inconvenience. To address this issue, an injectable hydrogel system is developed that can provide sustained EX release at the injection site, reducing the need for daily injections. In this study, the electrospray technique is examine to form EX@CS nanospheres by electrostatic interaction between cationic chitosan (CS) and negatively charged EX. These nanospheres are uniformly dispersed in a pH‐temperature responsive pentablock copolymer, which forms micelles and undergoes sol‐to‐gel transition at physiological conditions. Following injection, the hydrogel gradually degraded, exhibiting excellent biocompatibility. The EX@CS nanospheres are subsequently released, maintaining therapeutic levels for over 72 h compared to free EX solution. The findings demonstrate that the pH‐temperature responsive hydrogel system containing EX@CS nanospheres can be a promising platform for the treatment of T2D.