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.

Atherosclerosis, characterized by plaque buildup in arteries, is a major cause of cardiovascular mortality globally. Despite advances in diagnostics and interventions over the past few decades, the treatment options and outcomes remain far less than optimal. Nanotechnology has demonstrated emerging success in clinical settings; however, a potent targeted nanotherapeutic for atherosclerosis remains underdeveloped. In this study, we designed a new class of nanocarriers mimicking circulating monocyte features to enhance the site-specific delivery of theranostic agents for atherosclerosis. We first synthesized polymeric cores encapsulating a fluorescent payload with a modified nanoprecipitation method and cloaked the polymeric cores (NPs) with the plasma membrane fraction isolated from mouse monocytes. Our characterization results verified that NP cores are covered with a uniform lipid layer and that the resulting monocyte-mimicking nanoparticles (MNPs) retain the membrane proteins on their surface and have a similar value of zeta potential as monocytes. Both MNPs and NPs did not exhibit any hemotoxicity in vitro ; however, when incubated with cultured human vascular endothelial cells (ECs), MNPs showed a significantly higher uptake efficiency by ECs than NPs. Moreover, our in vivo studies with ApoE-knockout mice indicates that MNPs accumulated only in the atherosclerotic arteries but no other areas of the vasculature when administered intravenously. To summarize, our findings strongly support that monocyte membrane cloaking facilitates the nanoparticle attachment to atherosclerotic regions and enhances the entry of nanoparticles into the inflammatory endothelium in the arteries, suggesting that MNPs would serve as an excellent delivery strategy for targeted atherosclerosis therapy.

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