Au nanocluster-modulated macrophage polarization and synoviocyte apoptosis for enhanced rheumatoid arthritis treatment

The persistent progression of synovial inflammation and cartilage destruction contributes to the crosstalk between pro-inflammatory macrophages and activated fibroblast-like synoviocytes (FLSs) in a synovial microenvironment. In this work, structurally well-defined Au₂₅ nanoclusters were synthesized to induce phenotypic polarization of pro-inflammatory macrophages and apoptosis of activated FLSs for enhanced rheumatoid arthritis treatment. These ultra-small nanoclusters significantly modulated phenotypic polarization of a pro-inflammatory M1 phenotype to an anti-inflammatory phenotype M2 for relieving inflammation. Additionally, Au₂₅ nanoclusters can efficiently activate reactive oxygen species (ROS)-mediated apoptotic signaling pathways by inactivating thioredoxin reductase (TrxR), resulting in imbalance of the cellular redox homeostasis and initiation of FLS apoptosis. In an adjuvant-induced arthritis rat model, Au₂₅ nanoclusters efficiently ameliorated the hyperplasia of the synovium and reduced inflammatory cell infiltration with negligible side effects. This study provided a new insight into Au nanoclusters for treating rheumatoid arthritis.