An orally-administered nanotherapeutics with gold nanospheres supplying for rheumatoid arthritis therapy by re-shaping gut microbial tryptophan metabolism

Dysbiosis of gut microbiota significantly exacerbates the progression of rheumatoid arthritis (RA). Targeting gut microbiota may present a promising therapeutic strategy for RA. Gold nanospheres (GNS), known for excellent biocompatibility, stability and minimal toxicity, have emerged as precise modulators of gut microbiota, reshaping intestinal environments to treat various inflammatory diseases. Our study found that oral administration of 60-nm GNS effectively ameliorated collagen-induced arthritis (CIA) in mice, with a marked reduction in disease severity and synovial inflammation. Specifically, GNS notably enriched the probiotic genus Ligilactobacillus while restoring intestinal barrier function by upregulating tight junction proteins Claudin-1 and ZO-1. Targeted metabolomics analysis revealed GNS substantially increased the production of indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA) in gut, which were shown to activate the aryl hydrocarbon receptor (AhR) pathway. Mechanistic studies demonstrated that the IPA/IAA mixture inhibited PTEN ubiquitination, stabilizing PTEN protein levels and suppressing NF-κB activation in synovial tissues. These changes correlated with reduced synovial hyperplasia and inflammatory infiltration. Our findings established GNS as an effective nanomodulator of the gut-joint axis, providing novel insights into microbiota-targeted therapies for RA and other inflammatory diseases. Graphical abstract