Glucose-Responsive and Sustained Insulin-Releasing G-quartet/Protein Hydrogel Promotes Week-Long Normoglycemia in DiabeticRats

Diabetes remains a major global health burden, necessitating advanced therapies beyond insulin injections, such as closed-loop systems mimicking pancreatic beta-cell function. To address the limitations of current glucose-responsive insulin delivery platforms, particularly limited injectability and suboptimal biocompatibility, we developed injectable, glucose-responsive G-quartet/protein hydrogels (GPHGs) via supramolecular self-assembly and iminoboronate chemistry. GPHGs exhibit tunable viscoelasticity, with storage moduli ranging from 17 to 50 kPa across three formyl-phenylboronic acid (FPBA)-based crosslinkers (2FPBA, 3FPBA, and 4FPBA), thereby imparting structural integrity and stimulus responsiveness to the network. Under high glucose conditions (100 mM glucose), GPHG derived using 2FPBA exhibited a 0.28-fold decrease in storage modulus ( G ′) and a 0.21-fold reduction in loss modulus ( G ″), indicating glucose-mediated softening of the network. This mechanical response corresponds with accelerated insulin release, yielding ∼85% insulin release in 24 h under 100 mM glucose compared to ∼45% insulin release under 0 mM glucose. GPHG1 exhibits remarkable self-healing and negligible cytotoxicity at a concentration of 10 mg/mL in HaCaT, MCF7, and HCT116 cells. In type 1 diabetic rats, insulin-loaded GPHG1 sustained normoglycemia (120−150 mg/dL or 6.6−8.3 mM) for up to seven days, outperforming subcutaneous insulin. These findings highlight GPHG as a minimally invasive strategy for innovative insulin delivery systems, harnessing macromolecular and supramolecular design to advance blood glucose control.