Mitochondrial-targeted ROS scavenger delivery using selenium-doped layered double hydroxide nanocomposites for enhanced osteoarthritis therapy via inflammation suppression and macrophage metabolism reprogramming

Osteoarthritis (OA) is a chronic joint disorder characterized by synovial inflammation, cartilage degradation and macrophage polarization imbalance, where excessive reactive oxygen species (ROS) accumulation and mitochondrial dysfunction exacerbate pro-inflammatory M1 macrophage polarization. Here, a pH-responsive nanocomposite (Se/LDH@PEG-M) is developed by integrating selenium (Se) within MgAl-layered double hydroxide (MgAl-LDH), modified with PEGylation and loaded with the mitochondria-targeted antioxidant Mito-TEMPO. The synthesized nanocomposite retains glutathione peroxidase (GPX)-like activity and the antioxidant capacity of Se nanoparticles, while exhibiting pH-responsive degradation to neutralize acidic OA microenvironments and release Mg²⁺, Se and Mito-TEMPO for inflammation suppression, ROS scavenging and macrophage polarization modulation. In vitro, Se/LDH@PEG-M effectively inhibits pro-inflammatory M1 polarization while promoting anti-inflammatory M2 phenotypes by suppressing multiple inflammatory pathways, restoring redox homeostasis, and enhancing mitochondrial oxidative phosphorylation and ATP production via respiratory chain activation. Conditioned medium from Se/LDH@PEG-M-treated macrophages attenuates chondrocyte apoptosis, inflammation and catabolism compared to LPS group. In murine OA models, intra-articular Se/LDH@PEG-M administration effectively alleviates synovial inflammation, suppresses osteophyte formation and mitigates cartilage degradation. This multifunctional nanocomposite concurrently targets OA pathogenesis through macrophage immunomodulation, ROS scavenging and mitochondrial protection, providing a potential therapeutic strategy for OA management. Schematic illustration of the synthesis process and therapeutic mechanism of Se/LDH@PEG-M. ( A )The synthesis procedure of Se/LDH@PEG-M nanocomposites. The nanocomposites were developed by integrating selenium (Se) into Mg-Al layered double hydroxides, followed by PEG modification and loading with mitochondria-targeted antioxidant Mito-TEMPO. ( B ) The therapeutic mechanism of Se/LDH@PEG-M. The nanocomposites degraded in acidic OA microenvironments and releasing Mg²⁺, Se and Mito-TEMPO for inflammation suppression, ROS scavenging and immunomodulation.