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bioRxiv · 10.1101/2023.04.24.537992

Lesion-specific suppression of YAP/TAZ by biomimetic nanodrug ameliorates atherosclerosis development

Huang, H.-C.·Wang, T.-Y.·Rousseau, J.·Mungaray, M.·Michaud, C.·Plaisier, C.·Chen, Z. B.·Wang, K.-C.
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Abstract

Atherosclerosis, characterized by the buildup of lipid-rich plaque on the vessel wall, is the primary cause of myocardial infarction and ischemic stroke. Recent studies have demonstrated that dysregulation of yes-associated protein 1 (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 drug delivery vehicle targeting activated endothelium lining the plaque surface and utilizes MoNP to deliver verteporfin (VP), a potent YAP/TAZ inhibitor, for lesion-specific treatment of atherosclerosis. The results reveal that MoNP significantly enhance payload delivery to inflamed endothelial cells (EC) while avoiding phagocytic cells, and preferentially accumulate in atherosclerotic regions. MoNP-mediated delivery of VP substantially reduces YAP/TAZ expression, suppressing inflammatory gene expression and macrophage infiltration in cultured EC and mouse arteries exposed to atherogenic stimuli. Importantly, this lesion-targeted VP nanodrug effectively decreases plaque development in mice without causing noticeable histopathological changes in major organs. Collectively, these findings demonstrate a plaque-targeted and pathway-specific biomimetic nanodrug, potentially leading to safer and more effective treatments for atherosclerosis.

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Huang, H.-C., Wang, T.-Y., Rousseau, J., Mungaray, M., Michaud, C., Plaisier, C., Chen, Z. B., Wang, K.-C.. 2023-04-26. Lesion-specific suppression of YAP/TAZ by biomimetic nanodrug ameliorates atherosclerosis development. https://doi.org/10.1101/2023.04.24.537992

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