A Comprehensive Reactive-Oxygen-Species-Scavenging Metal-Organic Framework Orchestrates the AMPK-DOT1L-H3K79me3 Cascade to Alleviate Osteoarthritis.

Osteoarthritis (OA) is a complex pathological condition characterized by oxidative stress and progressive cartilage breakdown. The reciprocal relationship between the inflammatory joint milieu and impaired chondrocyte function drives the progressive deterioration of OA. Inspired by natural metalloenzymes that utilize metal ions as catalytic centers, stable metal-organic frameworks (MOFs) assembled from natural polyphenols and metal ions have emerged as promising candidates for mitigating inflammatory diseases. Nonetheless, numerous nanozymes are limited to restricted antioxidant capacity, failing to eliminate various kinds of reactive oxygen species (ROS). To address these limitations, we engineered the MnO2@UiO-66(Ce) (abbreviated as MCU) system, which was fabricated through the integration of MnO2 into nanoscale mesoporous UiO-66 MOFs for OA therapy. Within the MOF architecture, MnO2 coupled with Ce clusters establishes a continuous superoxide dismutase/catalase cascade reaction platform that enables efficient ROS scavenging. In vitro and in vivo experiments reveal that the MCU system significantly reduces intracellular ROS accumulation and ameliorates the inflammatory microenvironment, consequently attenuating cartilage matrix destruction. Further mechanistic investigations indicates that MCU alleviates OA progression through the epigenetic activation of Wnt/β-catenin via adenosine monophosphate-activated protein kinase-disruptor of telomeric silencing 1-like-mediated H3K79 methylation. In summary, this study suggests that this highly efficient cascade catalytic system may represent a promising strategic avenue for combating oxidative stress in chronic inflammatory diseases.