Abstract 134: Lesion-specific Suppression Of YAP/TAZ By Biomimetic Nanoparticles Ameliorates Atherosclerosis

Introduction: Recent evidence highlights the potential therapeutic benefit of targeting YAP/TAZ in mitigating atherosclerosis. However, challenges associated with systemic delivery hinder the translation of the mechanistic discovery into an effective treatment. This study aimed to address the challenges by developing a lesion-specific nanodrug to achieve site-specific inhibition of YAP/TAZ for atherosclerosis therapy. Hypothesis: We have formulated a novel monocyte membrane-coated nanoparticle (MoNP) platform designed to facilitate precise delivery of payloads to atherosclerotic arteries. Our hypothesis is that leveraging MoNP for the targeted delivery of verteporfin (VP), a potent YAP/TAZ inhibitor, will significantly enhance the efficacy in mitigating atherosclerosis. Methods: Polymeric nanoparticles containing VP were prepared using an emulsion approach, followed by enclosing them with plasma membranes isolated from monocytes, yielding MoNP-VP. The pharmacological effects of MoNP-VP were assessed on cultured vascular and immune cells, as well as in the atherosclerotic mouse model. Results: Our in vivo findings demonstrated that the administration of MoNP-VP, as opposed to free VP, led to a substantial reduction in arterial inflammation and plaque development, suggesting that VP delivered by MoNP is a more effective route than its free drug counterpart. To dissect the mechanisms of actions, we analyzed the arterial tissues post-treatment using scRNA-seq analysis. Our results identified 9 distinct cell clusters within the affected arteries. Specifically, MoNP-VP treatment led to a decrease in macrophage (MΦ) clusters and an increase in the cluster of smooth muscle cells (SMC). Furthermore, our in vitro assays confirmed the efficacies of MoNP-VP in reducing the atheroprone phenotypes. These include diminished endothelial cell activation, less proliferation and migration of SMC, and a reduction in foam cell formation from MΦ. Conclusion: Together, these findings support the notion that targeting YAP/TAZ dysregulation is a feasible strategy for reducing plaque development and progression and demonstrate that MoNP-VP is a highly effective nanodrug for treating atherosclerosis.