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‐κB 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.

Inflammation-induced bone erosion is a major pathological factor in several chronic inflammatory diseases that often cause severe outcomes, such as rheumatoid arthritis and periodontitis. Plenty of evidences indicated that the inflammatory bone destruction was attributed to an increase in the number of bone-resorbing osteoclasts. However, anti-resorptive therapy alone failed to prevent bone loss in an inflammatory condition. Conventional anti-inflammation treatments are usually intended to suppress inflammation only, but ignore debilitating the subsequent bone destruction. Therefore, inhibition of proinflammatory activation of osteoclastogenesis could be an important strategy for the development of drugs aimed at preventing inflammatory bone destruction. Methods: In this study, we synthesized a peptide coated gold cluster to evaluate its effects on inflammatory osteoclastogenesis in vitro and inflammation-induced bone destruction in vivo . The in vitro anti-inflammation and anti-osteoclastogenesis effects of the cluster were evaluated in LPS-stimulated and receptor activator of nuclear factor κB ligand (RANKL) stimulated macrophages, respectively. The LPS-induced expression of crucial pro-inflammation cytokines and RANKL-induced osteoclastogenesis as well as the activation of NF-κB pathway in both situations were detected. The inflammation-induced RANKL expression and subsequent inflammatory bone destruction in vivo were determined in collagen-immunized mice. Results: The gold cluster strongly suppresses RANKL-induced osteoclast formation via inhibiting the activation of NF-κB pathway in vitro . Moreover, treatment with the clusters at a dose of 5 mg Au/kg.bw significantly reduces the severity of inflammation-induced bone and cartilage destruction in vivo without any significant toxicity effects. Conclusion: Therefore, the gold clusters may offer a novel potent therapeutic stratagem for inhibiting chronic inflammation associated bone destruction.

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