A Biomimetic Lubricant Captures Hyaluronic Acid In Situ to Regenerate Cartilage: From Bench to Bedside

ABSTRACT Lubrication deficiency can lead to cartilage degeneration and osteoarthritis (OA), for which hyaluronic acid (HA) is limited by its short retention and reparative effect. Inspired by the natural cartilage lubrication mechanism, we propose a two‐step injection strategy to construct a biomimetic synergistic lubrication coating in situ on cartilage surfaces. The administration of developed cationic biomimetic lubricant (CS‐g‐PM) as the first injection to capture the subsequently administered HA via in situ self‐assembly on the cartilage surface, forming a natural cartilage‐like lubrication layer. In vitro, this strategy reduced friction coefficients to normal cartilage levels in OA human cartilage. Moreover, sequential CS‐g‐PM and HA articular‐injection in OA rats extended HA retention 5‐fold versus HA alone; meanwhile, regeneration of cartilage was synergistically promoted. Importantly, a first‐in‐human pretrial demonstrated rapid MRI‐evident cartilage repair at 1 month. At 6 months of follow‐up, patients showed sustained functional improvement and halted structural degeneration. This strategy offers a transformative solution for OA treatment.