Glucose-Responsive G-quartet/Protein hydrogels for Smart Insulin Delivery

The rising global burden of diabetes necessitates the development of advanced therapeutic strategies beyond conventional insulin therapies, which often fail to achieve precise glycemic control and are associated with pain and inconvenience to patients. This limitation is predominantly observed in Type 1 diabetes, an autoimmune disease that destroys insulin-producing β cells, leading to a lifelong dependence onexogenous insulin administration. These challenges underscore the critical need for glucose-responsive systems capable of autonomous and precise insulin delivery. In an effort to address this challenge, we have designed an injectable, glucose-responsive G-quartet/protein hydrogel (GPHG) engineered via supramolecular self-assembly and dynamic iminoboronate chemistry for smart insulin delivery. The system involves a supramolecular interaction (such as pi-po interaction) as well as dynamic iminoboronate ester chemistry to enable selective insulin release under hyperglycemic conditions, as evidenced by a insulin release assay/self-regulated pulsatile release pattern under cyclic glucose concentration. GPHGs demonstrate tunable viscoelasticity ranging from 10 to 50 kPa depending on the phenyl boronic acid-based crosslinkers. The developed system exhibits injectability, shear thinning behavior, non-cytotoxicity, mechanical flexibility, and controlled insulin release under physiologically relevant conditions. Furthermore, in vivo studies and histological investigations demonstrate effective glycemic regulation without adverse effects, highlighting its potential as a minimally invasive, translational platform for smart insulin delivery.