Nanoarchitectonics of Cartilage-Targeting Hydrogel Microspheres with Reactive Oxygen Species Responsiveness for the Repair of Osteoarthritis

Clinically, intra-articular administration can hardly achieve the truly targeted therapy, and the drugs are usually insufficient to show local and long-term therapeutic effects because of their rapid clearance. Herein, inspired by the phenomenon that bees track the scent of flowers to collect nectar, we developed cartilage-targeting hydrogel microspheres with reactive oxygen species (ROS)-responsive ability via combining the microfluidic method and photopolymerization processes to integrate cartilage-targeting peptides and ROS-responsive nanoparticles in the hydrogel matrix. The hydrogel microspheres with cartilage-targeting properties promoted better retention in the joint cavity and enhanced cellular uptake of the nanoparticles. Moreover, the ROS-responsive nanoparticles could react with osteoarthritis (OA)-induced intracellular ROS, resulting in the depolymerization of nanoparticles, which could not only eliminate excess ROS and reduce inflammation but also promote the release of dexamethasone (Dex) and kartogenin (KGN) in situ, realizing effective OA therapy. It was demonstrated that this hydrogel microsphere showed favorable ROS-responsive ability and enhanced chondrogenic differentiation as well as the downregulation of pro-inflammatory factors in vitro. Additionally, the hydrogel microspheres, similar to bees, could target and effectively repair cartilage in the OA model. Thus, the injectable hydrogel microspheres exerted an excellent potential to repair OA and may also provide an effective avenue for inflammatory bowel disease therapy.