<p>Atherosclerotic lesions contain heterogeneous macrophage populations with divergent functional phenotypes that play opposing roles in disease progression, creating a major obstacle for the development of macrophage-targeted therapy. The identification of novel molecules that exhibit both preferential expression and functional activity in inflammatory plaque macrophages is crucial for the development of more specific anti-inflammatory therapies against atherosclerosis. Here, we report that the expression of C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical chemokine receptor initially cloned from LPS-activated macrophages, progressively increased in atherosclerotic lesions during disease progression in both human and mouse models, with predominant expression in inflammatory macrophages characterized by high expression of NLRP3 inflammasome components. Moreover, specific deletion of hematopoietic CCRL2 attenuated atherosclerotic progression in <i>Apoe</i>^<i>-/-</i> mice fed a high-cholesterol diet, as evidenced by significant decreases in plaque burden, macrophage accumulation, and NLRP3 inflammasome activation within the plaques, without affecting blood lipid levels. Mechanistically, ox-LDL or other danger signals induce macrophages to express CCRL2, which can be endocytosed and relocalized to early endosomes, where it interacts with NLRP3 to promote inflammasome assembly and activation. Importantly, macrophage-targeted nanoparticle delivery of <i>Ccrl2</i>-siRNA effectively attenuated atherosclerotic progression in vivo, concomitant with reduced levels of IL-1β, the key effector cytokine of the NLRP3 inflammasome, and diminished macrophage accumulation within plaques. Taken together, the results of our study establish CCRL2 as both a new marker for identifying inflammatory macrophages and a promising anti-inflammatory therapeutic target for atherosclerosis through the modulation of aberrant NLRP3 inflammasome activation in pathogenic inflammatory macrophages.</p>