Abstract

Osteoarthritis (OA) is the most common degenerative joint disease, which is largely driven by the deterioration of cartilage lubrication. However, current lubricants, such as hyaluronic acid (HA), suffer from poor mechanical resilience and rapid enzymatic degradation. Herein, we develop a structurally engineered lubricant, HPG-g-pSBMA (HgS), constructed by grafting zwitterionic poly(sulfobetaine methacrylate) (pSBMA) chains onto a globular hyperbranched polyglycerol (HPG) core. The hyperbranched topology minimizes molecular entanglement and shear thinning, while the dense zwitterionic shell forms a robust hydration layer that resists compression and frictional wear. HgS exhibits superior lubrication efficacy at a low concentration (1 mg/mL) with enhanced injectability, significantly outperforming 10 mg/mL HA. Molecular simulations reveal strong hydration shell formation and hydration-mediated disruption of solute–solute interactions. HgS demonstrates excellent biocompatibility and enzymatic stability, prolonged intra-articular retention, and effective inhibition of OA progression in vivo. This work highlights a topology-guided design strategy for durable and efficient joint lubricants for OA treatment.