The supramolecular dynamic hydrogel functionalized with rhein for the treatment of osteoarthritis through mechanical reinforcement, anti-inflammatory modulation, and pH responsiveness.

Hydrogels have shown promise in osteoarthritis (OA) treatment due to their tissue-like properties, but many suffer from poor mechanical strength, limited stimuli-responsiveness, and insufficient ability to regulate the inflammatory microenvironment. To overcome these challenges, we developed an oxidized dextran/polyethyleneimine-rhein (PEI-RH) hydrogel. Rhein, a natural anthraquinone polyphenol, was covalently grafted onto polyethyleneimine (PEI), introducing hydrogen bonding and π-π stacking sites. Its exposed phenolic hydroxyl groups and anthraquinone moieties endowed the hydrogel with intrinsic ROS-scavenging and anti-inflammatory capacity. Crosslinking with oxidized dextran (OXD) via Schiff-base reaction formed a multi-level dynamic network, enhancing gelation speed (1.7×), compressive modulus (1.9×), tensile modulus (1.7×), and self-healing. The hydrogel exhibited pH-responsive release of PEI-RH macromolecules, efficient ROS scavenging, and potent anti-inflammatory activity. Incorporation of a collagen-mimetic peptide (GFOGER) further promoted cartilage regeneration. In vitro, the hydrogel reduced oxidative stress, suppressed inflammation, and supported chondrocyte function. In vivo, it significantly improved cartilage repair in OA models. This multifunctional hydrogel, integrating small-molecule bioactivity with dynamic crosslinking, offers a robust platform for OA therapy.