Rebaudioside-A aortic atherosclerotic Xanthatin lesions from LDL-receptor/MCP-1 double-knockout mice showed less lipid deposition and fewer macrophages, which suggests that MCP-1 is related to plaque instability. In addition, MCP-1 induced tissue-factor expression in smooth muscle cells and Thelper 1 cells, suggesting that MCP-1 has a procoagulant function. Based on available experimental evidence, it is logical to speculate that MCP-1 offers a promising target for the treatment of vulnerable plaques. The RNAi method selectively and efficiently silences mRNA for a wide range of proteins and has been used in experimental studies for treating or preventing several diseases. Two of the most important considerations for developing RNAi as a feasible therapy are first, devising efficient mechanisms for delivery of small-interfering RNA to the target cells in vivo, and second, avoiding nonspecific or off-target effects of the siRNA. However, with the systemic delivery method, biodistribution of radiolabeled siRNA in mice demonstrated that most of the siRNA accumulated in the liver and kidneys. Lewis et al showed that systemic coinjection of luciferase reporter plasmids with siRNA luciferase resulted in strong inhibition of luciferase activity not only in the liver but also in kidney, spleen, lung, and pancreas of postnatal mice, which suggests that in mammals, siRNA can be delivered effectively into many organs after systemic application. In order to achieve high-titer rAd5-shRNA in the carotid plaque, we used a site-specific delivery method by spreading the adenovirus suspension around the adventitia of the carotid artery, which was incubated for 20 min at room temperature. Previous studies have demonstrated that site-directed silencing of gene expression is effective and efficient. Furthermore, the inhibitory effects of MCP-1 lasted for two weeks. To assess the nonspecific or off-target effects of this siRNA delivery method, we examined EGFP expression in the heart, liver and kidney and found little expression of EGFP in these organs, which suggested that the siRNA site-specific delivery method was safe and did not affect primary organs other than the targeted vessels. In our previous study, we found that dominant-negative mutation of MCP-1 attenuated atherosclerotic lesion progression and prevented vulnerable aortic plaques from rupture in a rabbit model. In the present study, we obtained similar results in a mouse model of vulnerable plaque and found that Ad-MCP-1-shRNA treatment reduced the MCP-1 gene expression to a greater extension than plRES-EGFP7ND treatment. Recent studies found that siRNA treatment was as effective as antisense oligonucleotide treatment in both in vitro and in vivo experiments.