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<p>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.</p> Graphical Abstract <p>Schematic illustration of the synthesis process and therapeutic mechanism of Se/LDH@PEG-M. (<b>A</b>)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>B</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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月31日

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  • Xuan Fang,
  • Hongqi Zhao,
  • Wentao Ke,
  • Yi Zou,
  • Tao Xu,
  • Guangzi Chen,
  • Jian Li,
  • Gaohong Sheng,
  • Haozhe Cheng,
  • Hao Zhu,
  • Jun Xiao,
  • Wei Seong Toh,
  • Sien Lin,
  • Tianqi Wang,
  • Tian Ma

摘要

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.

Graphical Abstract

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.