Senescent cells drive atherosclerosis at all stages and contribute to cardiovascular disease. However, the markers in these senescent aortic plaques have not been well studied, creating a huge obstacle in the exploration of a precise and efficient system for atherosclerosis treatment. Recently, CD9 has been found to induce cellular senescence and aggravated atherosclerotic plaque formation in apolipoprotein E knockout (ApoE-/-) mice. In the present study, this result has been leveraged to develop CD9 antibody-modified, hyaluronic acid-coated mesoporous silica nanoparticles with a hyaluronidase-responsive drug release profile. In invitro models of senescent foamy macrophages and senescent endothelial cells stimulated with oxidized high-density-lipoprotein, the CD9 antibody-modified mesoporous silica nanoparticles exhibit high cellular uptake; reduce the reactive oxygen species level, high-density lipoprotein oxidation, and production of TNF-α and IL-6; and attenuate the senescence process, contributing to improved cell viability. In vivo experiment demonstrated that these nanoparticles can successfully target the senescent lesion areas, deliver the anti-senescence drug rosuvastatin to the senescent atherosclerotic plaques (mainly endothelial cells and macrophages), and alleviate the progression of atherosclerosis in ApoE-/- mice. By providing deep insight regarding the markers in senescent atherosclerotic plaque and developing a nano-system targeting this lesion area, the study proposes a novel and an accurate therapeutic approach for mitigating atherosclerosis through senescent cell clearance.
Keywords: Atherosclerosis; CD9; Foamy macrophage; Mesoporous silica nanoparticles; Senescence.
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