Abstract

RNA interference, mediated by small interfering RNA (siRNA), is effective in silencing genes with a high degree of specificity. To explore the therapeutic potential of systemically administered siRNA for rheumatoid arthritis (RA), we tested the complex of siRNA and the recently developed wrapsome (siRNA/WS), containing siRNA encapsulated liposome, in mice with collagen-induced arthritis (CIA). Mice with CIA received intravenous injection of Cy5-labeled siRNA/WS. Fluorescence stereoscopic microscopy and flow cytometry were used to assess the siRNA/WS tissue distribution. The efficacy of siRNA targeting tumor necrosis factor (TNF)-α/WS in CIA was evaluated by arthritis score. TNF-α mRNA levels in the joints were measured by real-time reverse transcriptase-polymerase chain reaction. The intensity of Cy5-fluorescence was higher in arthritic joints than in non-arthritic sites in Cy5-siRNA/WS-treated mice, and remained higher up to 48 hrs post-injection, compared with naked Cy5-siRNA-treated mice. Cy5-fluorescence intensity was higher in synovial cells than splenocytes, bone marrow cells and peripheral blood leukocytes. The majority of Cy5-positive synovial cells were CD11b+ with only a few CD3+ cells. Treatment with TNF-α siRNA/WS resulted in significant decreases in severity of arthritis and TNF-α mRNA level in the joints compared with control siRNA/WS. In conclusion, the use of our WS allowed efficient and targeted delivery of siRNAs to arthritic joints. The siRNA/WS was mainly incorporated into CD11b+ cells, including macrophages and neutrophils, in the inflamed synovium, suggesting its potential therapeutic effects in RA by silencing the expression of inflammatory molecules produced by these cells.