Selenium nanozymes effectively treat rheumatoid arthritis by specifically activating selenoproteins to block oxidative damage and cGAS–STING signaling pathway

Redox imbalance has become an important factor in rheumatoid arthritis (RA) progression , previous studies showed selenium nanozymes (Se NPs) effectively treated RA by restoring redox. However, the process of Se NPs regulates RA, especially the mechanism of Se NPs activates selenoproteins in inhibiting inflammation remains unclear. Herein, the redox imbalance in RA patients was first analyzed, and selenoproteins associated with macrophage inflammation were identified via mRNA profiling. Subsequently, the synthesized Se NPs with glutathione peroxidase (GPX)-like activity as a supplement, and it was found that Se NPs specially upregulate selenoproteins in macrophages applied to in vitro and in vivo models, furthermore combined with GPX-like activity, Se NPs quickly eliminated reactive oxygen and nitrogen species (RONS), restored redox homeostasis in RA, and alleviated symptoms of RA by effectively inhibiting macrophage inflammation. The mechanistic study showed that Se NPs effectively prevent mitochondrial and nDNA damage by specifically activating selenoproteins, blocking the interaction between DNA and cyclic GMP–AMP synthase (cGAS), and restraining the activation of cGAS–stimulator of interferon genes (STING) and nuclear factor kappa-B (NF- κ B) pathway, thus effectively suppressing macrophage inflammation and treating RA. Therefore, this study reveals the mechanism by which Se NPs inhibit macrophage inflammation, providing a new potential therapeutic target for treating inflammatory diseases.