Metformin-hydrogel with glucose responsiveness for chronic inflammatory suppression

Abstract Diabetes-induced chronic inflammation accelerates tissue degeneration and is difficult to cure due to the persistent pathological high-glucose microenvironment. Herein, a glucose-responsive drug delivery system was constructed by conjugating phenylboronic acid on the surface of liposomes via membrane insertion and further crosslinked into a glucosamine-modified hydrogel composed of hyaluronic acid (HA) and poly(ethylene glycol) diacrylate (PEG) through borate linkages to deliver metformin, which could achieve the anti-inflammation effect under high glucose condition (Met@HA-PEG).The release kinetics results revealed that Met@HA-PEG could adjust the amount of metformin by responding to the change of glucose concentrations. It is proved that Met@HA-PEG could protect mitochondria from ROS, thereby inhibiting the activation of the NLRP3 inflammatory pathway and finally increasing the synthesis of extracellular matrix (ECM) in the nucleus pulposus cells compared to the high glucose-treated group. In vivo experiments showed that Met@HA-PEG could effectively promote tissue regeneration in the diabetes-induced intervertebral disc degeneration model rats by inhibiting high glucose-induced chronic inflammation and stimulating ECM synthesis. Overall, a drug delivery system with glucose sensitivity was designed to achieve the spatiotemporal release of metformin, the long-term anti-inflammation and promotion of ECM synthesis which ensures the smooth completion of tissue regeneration under diabetic conditions.