Super-small　nanoclusters　may　intrinsically　trigger　specific　molecular　pathway　for　disease　treatment　in　vitro/vivo.　To　prove　the　hypothesis　the　super-small　nanoclusters,　e.g.,　Au　clusters,　are　directly　used　to　treat　rheumatoid　arthritis　(RA)　in　vitro/vivo.　RA　is　a　chronic　autoimmune　disease　that　is　characterized　by　the　inflammation　of　joints　and　the　unreversible　destruction　of　the　cartilage/bone.　Au　clusters　significantly　suppress　lipopolysaccharide　(LPS)-induced　proinflammatory　mediator　production　in　the　murine　macrophage　cell　line　by　inhibiting　the　signaling　pathways　that　regulate　the　major　proinflammatory　mediator　genes.　In　preclinical　rat　RA　studies,　Au　clusters　strongly　prevent　type　II　collagen-induced　rat　RA　without　systemic　side　effects.　Compared　with　the　clinical　first-line　anchored　anti-RA　drug,　methotrexate,　Au　clusters　equally　inhibit　inflammation　in　vivo.　Type　II　collagen-induced　rat　RA　is　characterized　with　the　destruction　of　cartilage/bone;　treatment　with　Au　clusters　reverses　the　destruction　of　cartilage/bone　to　its　normal　state.　This　is　because　Au　clusters　directly　inhibit　receptor　activator　of　nuclear　factor-kappa　B　ligand　(RANKL)-induced　osteoclast　differentiation　and　function　through　the　downregulation　of　osteoclast-specific　genetic　marker　expression.　However　the　methotrexate　almost　has　no　positive　effect　for　this　key　issue　in　rat　RA　therapy.　These　data　prove　that　the　super-small　nanoclusters,　e.g.,　Au　clusters,　could　be　a　novel　candidate　nanodrug　for　RA　treatment.