...Previously, we reported that 5-aminolevulinic acid-mediated sonodynamic therapy (SDT) promotes apoptotic cell efferocytosis via ATP release in atherosclerotic plaques. However, the exact signaling molecule involved in this process is still unknown. In the present study, sinoporphyrin sodium-mediated SDT (DVDMS-SDT) was applied to balloon-denuded rabbits in vivo to observe changes in the composition of atherosclerotic lesions. Cultured human THP-1-derived and mouse peritoneal macrophage-derived foam cells were used for in vitro mechanistic studies. Three days after DVDMS-SDT treatment, macrophage efferocytosis was significantly enhanced whereas local inflammation was attenuated in rabbit atherosclerotic lesions. At days 7 and 28, the histopathological analysis showed that DVDMS-SDT inhibited the progression of atherosclerosis, reduced the macrophage content, and increased the smooth muscle cell content in a time-dependent manner. Mechanistically, DVDMS-SDT activated mitochondria-caspase apoptosis in foam cells. Interestingly, activated by DVDMS-SDT, caspase-3 a key factor of apoptosis, reduced the expression of the anti-phagocytic molecule CD47 in foam cells. Of great importance, the promotion of macrophage efferocytosis by DVDMS-SDT can be eliminated by the overexpression of CD47. Overall, these results demonstrated that DVDMS-SDT effectively boosted efferocytosis via deactivation of CD47 expression, thereby reducing inflammation in advanced atherosclerotic plaques.