Multi‐Responsive Dendrimer‐Hyaluronic Acid Hydrogel With Lubricating and Immunoregulatory Functions for Synergistic Osteoarthritis Therapy

ABSTRACT Osteoarthritis (OA) progression is driven by inflammation, oxidative stress, and mechanical wear. However, current therapies are often limited in efficacy due to poor biocompatible functional materials and the inability to deliver drugs on demand in the pathological joint. Herein, we developed a triple‐responsive, nanostructured injectable hydrogel (Cur/GP‐HA) to OA joint microenvironment for synergistic treatment. The Cur/GP‐HA hydrogel was formed by cross‐linking hyaluronic acid (HA) with curcumin (Cur)‐preloaded, phenylboronic acid‐modified generation 3 poly(amidoamine) dendrimers, utilizing the dynamic covalent chemistry between diols on HA and PBA under a physiological pH. This hydrogel exhibited a 3D porous network with excellent injectability and self‐healing ability, enabling intelligent Cur release in response to low pH, high reactive oxygen species (ROS) generation, or mechanical compression. Importantly, the constructed Cur/GP‐HA hydrogel removed ROS, promoted the polarization of macrophages, and regulated cytokine secretion to reshape the anti‐inflammatory microenvironment. In vivo, intra‐articular injection of Cur/GP‐HA hydrogel significantly reduced cartilage erosion, alleviated joint inflammation, and improved subchondral bone integrity. In addition, the synergistic combination of HA lubrication and sustained Cur release provided chondroprotection and anti‐wear effects. This work proposes an intelligent injectable hydrogel integrating antioxidant, immunomodulatory, and mechano‐responsive protective functions, providing a promising new strategy for OA treatment.