Reprogramming Mitochondrial Metabolism in Synovial Macrophages of Early Osteoarthritis by a Camouflaged Meta‐Defensome

Osteoarthritis (OA) is a low‐grade inflammatory and progressive joint disease, and its progression is closely associated with an imbalance in M1/M2 synovial macrophages. Repolarizing pro‐inflammatory M1 macrophages into the anti‐inflammatory M2 phenotype is emerging as a strategy to alleviate OA progression but is compromised by unsatisfactory efficiency. In this study, the reprogramming of mitochondrial dysfunction is pioneered with a camouflaged meta‐Defensome, which can transform M1 synovial macrophages into the M2 phenotype with a high efficiency of 82.3%. The meta‐Defensome recognizes activated macrophages via receptor–ligand interactions and accumulates in the mitochondria through electrostatic attractions. These meta‐Defensomes are macrophage‐membrane‐coated polymeric nanoparticles decorated with dual ligands and co‐loaded with S‐methylisothiourea and MnO2. Meta‐Defensomes are demonstrated to successfully reprogram the mitochondrial metabolism of M1 macrophages by scavenging mitochondrial reactive oxygen species and inhibiting mitochondrial NO synthase, thereby increasing mitochondrial transcription factor A expression and restoring aerobic respiration. Furthermore, meta‐Defensomes are intravenously injected into collagenase‐induced osteoarthritis mice and effectively suppress synovial inflammation and progression of early OA, as evident from the Osteoarthritis Research Society International score. Therefore, reprogramming the mitochondrial metabolism can serve as a novel and practical approach to repolarize M1 synovial macrophages. The camouflaged meta‐Defensomes are a promising therapeutic agent for impeding OA progression in tclinic. The relationship between mitochondrial dysfunction and osteoarthritis (OA) severity is established and an effective strategy for reprogramming the mitochondrial metabolism is pioneered, through a novel camouflaged dual‐targeting meta‐Defensome, comprising macrophage‐membrane‐cloaked polymeric nanoparticles loaded with double nanoenzymes that scavenge mitochondrial reactive oxygen species and inhibit mitochondrial nitric oxide synthase, efficiently restoring the M1/M2 macrophage imbalance in the synovium and impeding OA progression.