Copper-based nanocatalyst with macrophage membrane coating enables context-dependent redox regulation for osteoarthritis

Osteoarthritis (OA) is a heterogeneous whole-joint disease involving complex interactions between stromal and immune cells. Although reactive oxygen species (ROS) contribute to OA progression, different pathogenic cell populations exhibit distinct redox requirements, creating challenges for conventional antioxidant or pro-oxidative therapies. Here, we develop a macrophage membrane-coated copper-based nanocatalyst (MM@CuRB) that enables context-dependent redox reprogramming for OA therapy. MM@CuRB integrates Cu-mediated catalytic activity, rosmarinic acid (RA)-mediated antioxidant regulation, and MM-associated biological recognition within a dynamic Cu–RA–BDBA coordination nanoplatform. The physicochemical properties, cellular responses, therapeutic effects, and tissue-level molecular changes of MM@CuRB were evaluated using primary fibroblast-like synoviocytes, bone marrow-derived macrophages, a papain-induced rabbit OA model, and bulk transcriptomic analysis. In IL-1β-activated FLS, MM@CuRB enhanced radical-associated oxidative stress, mitochondrial dysfunction, and apoptosis-associated responses. In contrast, the same nanoplatform reduced excessive intracellular ROS, suppressed MyD88–NF-κB-associated inflammatory signaling, and promoted a less inflammatory and more reparative macrophage-associated marker profile in LPS-stimulated macrophages. In a chemically induced rabbit OA model, systemic administration of MM@CuRB attenuated synovial inflammation, cartilage matrix degradation, and subchondral bone alterations while showing favorable systemic tolerability under the tested conditions. Bulk transcriptomic analysis further revealed tissue-level suppression of inflammatory pathways and enrichment of apoptosis-associated programs after treatment. Collectively, this study provides a proof-of-concept demonstration that a single biomimetic nanoplatform can generate distinct redox outcomes according to cellular context, supporting the concept that net cellular redox responses are shaped by the interplay between material chemistry and cellular state. This framework highlights a potential strategy for coordinating divergent redox requirements therapeutically.