Thermosensitive Polypeptide Hydrogels as a Platform for ROS‐Triggered Cargo Release with Innate Cytoprotective Ability under Oxidative Stress

Reactive oxygen species (ROS) play important roles in cell signaling pathways, while increased production of ROS may disrupt cellular homeostasis, giving rise to a series of diseases. Therefore, materials responding to ROS at physiological levels are of great significance. In this work, a novel ROS‐responsive thermogelling hydrogel based on methoxy poly(ethylene glycol)‐poly( l ‐methionine) diblock copolymers is designed and synthesized. The mechanism for solution‐to‐hydrogel (sol‐gel) phase transitions of the copolymer aqueous solutions is studied. Incubation of the hydrogels in the presence of peroxide hydrogen (H 2 O 2 ) displays a H 2 O 2 ‐responsive degradation process. The hydrogels containing Rhodamine 6G exhibit sustained release profiles that are accelerated in response to H 2 O 2 . An innate cytoprotective ability of the hydrogels is revealed by incubation of L929 cells with the hydrogels under oxidative stress, which reduces H 2 O 2 ‐mediated cell death. ROS produced by activated macrophages can accelerate the erosion of the hydrogel, suggesting that the hydrogel is also responsive to pathological level of H 2 O 2 . Meanwhile, the poly( l ‐methionine)‐based hydrogels degrade within 6 weeks after subcutaneous injection into rats, with a good biocompatibility in vivo. Overall, the injectable, ROS‐responsive hydrogels may serve as promising platforms for sustained drug delivery and cell‐based therapies in treatment of diseases with local oxidative stress.