Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA.
Nat Commun. 2024 Sep 13;15(1):8034. doi: 10.1038/s41467-024-52005-1.
Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key 'don't-eat-me' molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors.
动脉粥样硬化是一种炎症性疾病，可导致心血管疾病。吞噬作用（巨噬细胞吞噬细胞的过程）的再激活已成为动脉粥样硬化的转化治疗靶点。系统性阻断关键的“别吃我”分子 CD47 可触发对凋亡血管组织的吞噬作用，并显著减少斑块负担。然而，它也会诱导红细胞清除，导致贫血。为了解决这个问题，我们之前开发了一种载有促进吞噬作用的化学抑制剂的巨噬细胞特异性纳米疗法。由于在小鼠研究中发现它是安全有效的，我们旨在将我们的纳米颗粒推进到动脉粥样硬化的猪模型中。在这里，我们证明可以在不损害纳米颗粒功能的情况下扩大生产规模。在疾病的早期阶段，我们发现我们的纳米疗法可减少动脉粥样硬化病变中凋亡细胞的积累和炎症。值得注意的是，这种疗法不会引起贫血，突出了靶向巨噬细胞检查点抑制剂的转化潜力。
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