Injectable and reactive oxygen species-responsive nanogel–microgel hybrid bio-lubricants for osteoarthritis therapy by immunometabolic reprogramming

Osteoarthritis (OA) is a common degenerative joint disorder involving irreversible cartilage damage, subchondral bone dysfunction, and chronic synovitis. Current intra-articular therapies suffer from short-lived effects and inadequate control of macrophage-mediated inflammation. To address this limitation, we develop an injectable, ROS-responsive nanogel–microgel hybrid bio-lubricant for OA treatment via immunometabolic reprogramming. Skatole-loaded mesoporous silica nanoparticles were crosslinked with polyvinyl alcohol to form ROS-responsive nanogels (Ska@NGs), which were subsequently encapsulated into HAMA/CSMA microgels using microfluidics as Ska@N-MGs. The physicochemical, rheological, lubricating, ROS-responsive, and biological properties of the system were evaluated in vitro, followed by therapeutic assessment in an ACLT + MMT-induced rat OA model. Ska@N-MGs exhibited favorable lubricating and ROS-regulating properties, with a friction coefficient of approximately 0.007. Skatole attenuated inflammatory responses in LPS-stimulated macrophages, while Ska@NGs treatment in the macrophage–chondrocyte co-culture system was accompanied by improved cartilage matrix-related markers. In a rat OA model, intra-articular injection of Ska@N-MGs reduced synovial inflammation and alleviated OA progression. This hybrid system integrates lubrication, stimuli-responsive drug delivery, and immunometabolic modulation, providing a promising platform for OA therapy.