A Nano‐Cocoon Platform Attenuates Osteoarthritis Progression via Chem‐Bio Coupled ROS Scavenging and Cartilage Lubrication Restoration

Excessive reactive oxygen species (ROS) accumulation, cartilage matrix degeneration, and impaired lubrication are central drivers of osteoarthritis (OA). However, poor matrix retention limits drug delivery to chondrocytes and lubrication restoration. Here, we develop a zwitterion‐based, thioketal‐crosslinked Superoxide Dismutase (SOD)‐polymer complex (SOD‐SADT) via in situ atom transfer radical polymerization, in which polymers grow from the enzyme surface and envelop SOD to form a nanoscale cocoon. The polymer shell exhibits cartilage‐matrix affinity through van der Waals and electrostatic interactions with type II collagen and chondroitin sulfate. Accordingly, its zwitterionic hydration layer enables matrix‐anchored lubrication, substantially reducing the coefficient of friction of OA‐like cartilages. Meanwhile, SOD‐SADT establishes a chem‐bio coupling for ROS elimination that couples enzymatic·O 2 − dismutation with thioketal‐triggered chemical depletion of H 2 O 2 and·OH, achieving up to ∼80% ROS scavenging. Notably, SOD‐SADT achieves high chondrocyte uptake (∼ 91.7 ± 3.4%) and promotes lysosomal escape. This enhances intracellular utilization, thereby attenuating oxidative injury and restoring anabolic/catabolic balance. In a mouse model of OA, intra‐articular SOD‐SADT preserves cartilage structure and improves joint function, thereby markedly slowing OA progression. Overall, this work offers a dual‐action strategy that couples intracellular antioxidant regulation with extracellular lubrication repair to address OA.