Atherosclerosis, a chronic inflammatory disease, is the primary cause of myocardial infarction and ischemic stroke. Recent studies have demonstrated that dysregulation of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) contributes to plaque development, making YAP/TAZ potential therapeutic targets. However, systemic modulation of YAP/TAZ expression or activities risks serious off-target effects, limiting clinical applicability. To address the challenge, this study develops monocyte membrane-coated nanoparticles (MoNP) as a targeted delivery system for activated and inflamed endothelium lining the plaque surface. The MoNP system is used to deliver verteporfin (VP), aimed at inhibiting YAP/TAZ specifically within arterial regions prone to atherosclerosis. The results reveal that MoNP significantly enhance payload delivery to inflamed endothelial cells (EC) while avoiding phagocytic cells. When administered in mice, MoNP predominantly accumulate in intima of the atheroprone artery. MoNP-mediated delivery of VP substantially reduces YAP/TAZ expression, thereby suppressing inflammatory gene expression and macrophage infiltration in cultured EC and mouse arteries exposed to atherogenic stimuli. Importantly, this targeted VP nanodrug effectively decreases plaque development in mice without causing noticeable histopathological changes in major organs. Collectively, these findings demonstrate a lesion-targeted and pathway-specific biomimetic nanodrug, potentially leading to safer and more effective treatments for atherosclerosis.

中文翻译：

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仿生纳米药物靶向炎症并抑制 YAP/TAZ 以改善动脉粥样硬化

动脉粥样硬化是一种慢性炎症性疾病，是心肌梗塞和缺血性中风的主要原因。最近的研究表明，yes 相关蛋白 (YAP) 和 PDZ 结合域 (TAZ) 转录共激活因子的失调有助于斑块的形成，使 YAP/TAZ 成为潜在的治疗靶点。然而，YAP/TAZ 表达或活性的系统调节存在严重的脱靶效应，限制了临床适用性。为了应对这一挑战，本研究开发了单核细胞膜涂层纳米粒子（MoNP）作为靶向递送系统，用于斑块表面内衬的激活和发炎的内皮。MoNP 系统用于输送维替泊芬 (VP)，旨在特别抑制容易发生动脉粥样硬化的动脉区域内的 YAP/TAZ。结果表明，MoNP 显着增强了向发炎内皮细胞 (EC) 的有效负载输送，同时避免了吞噬细胞。当给小鼠施用时，MoNP 主要积聚在易发生动脉粥样硬化的动脉内膜中。MoNP 介导的 VP 递送显着降低 YAP/TAZ 表达，从而抑制培养的 EC 和暴露于致动脉粥样硬化刺激的小鼠动脉中的炎症基因表达和巨噬细胞浸润。重要的是，这种靶向 VP 纳米药物可有效减少小鼠斑块的形成，而不会引起主要器官明显的组织病理学变化。总的来说，这些发现证明了一种针对病变和通路特异性的仿生纳米药物，有可能为动脉粥样硬化提供更安全、更有效的治疗方法。