Abstract Atherosclerosis is the leading cause of coronary heart disease and stroke. Sterile Inflammation, resulting from activation of the inflammasome NLRP3, plays a key role in the pathophysiology of atherosclerosis. Studies suggested that low-dose rIL-2 may be effective in treating autoimmune and inflammatory diseases by inducing Treg cells. Since rIL-2 has unfavorable pharmacokinetic profile in humans, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain, to extend the half-live of IL-2 for Treg expansion. In vitro treatment of human PBMCs with HCW9302 significantly expanded CD4+/CD25+/FoxP3+ Treg cells without activating CD4+ and CD8+ T cells over a broader concentration range than rIL2. Subcutaneous injection of HCW9302 (3 mg/kg every 2 – 3 weeks) into atherosclerosis-prone mice (ApoE−/− mice and LDLR−/− mice fed the Western Diet (WD) for 6 weeks) significantly increased the percentage of Treg cells, NK cells and CD8+ T cells in blood compared to the PBS-treated control group (p<0.001). Cytokines associated with atherosclerosis, including IL-1β and MCP-1, were also significantly decreased in the HCW9302-treated group, suggesting HCW9302 can moderate inflammasome NLRP3 activities. Remarkably, HCW9302 lowered the fasting blood glucose and insulin resistance. In aortas evaluated by the en face method at week 13 of WD, the ratio of plaque size to aortic surface was also significantly lower in HCW9302-treated mice compared to controls. HCW9302 treatment was well tolerated in both models. In summary, HCW9302 can effectively prevent the development of atherosclerosis in ApoE−/− mice and LDLR−/− mice, potentially through expansion of Treg cells.