A dual-functional hydrogel integrating adhesive and lubricating interfaces for mitochondrial protection–Driven cartilage regeneration

Osteoarthritis (OA) progression is driven by chronic inflammation, oxidative stress, and mitochondrial dysfunction, which together disrupt cartilage homeostasis and hinder regeneration. Here, we developed a paeoniflorin-loaded multifunctional hydrogel (AdHy@Pae) composed of 2-Hydroxyethyl methacrylate, sulfobetaine methacrylate, and sodium polyglutamate. The latter two components endowed the material with excellent adhesive properties, whereas the introduction of Pae provided abundant hydroxyl groups to decrease interfacial energy, resulting in superior lubrication under wet condition. More importantly, with sustained release of Pae and scavenge of ROS, AdHy@Pae alleviated oxidative injury, restored mitochondrial membrane potential, and preserved cell viability of chondrocyte. It also rebalanced extracellular matrix (ECM) metabolism and maintained cartilage phenotypic stability. In a rat OA model, intra-articular administration of AdHy@Pae markedly restored cartilage and subchondral bone architecture, as evidenced by improved trabecular continuity, smooth cartilage surfaces, and significantly reduced OARSI and Mankin scores. Transcriptomic profiling and network analysis revealed that AdHy@Pae reprograms mitochondrial dynamics homeostasis and inflammatory gene networks, notably suppressing IL-17A and TNF-α signaling. Collectively, AdHy@Pae provides a robust and durable strategy for precise cartilage protection and repair in osteoarthritis.