Monocyte-Mimetic Nanoparticle Delivery of Verteporfin Promotes Plaque-Stabilizing Remodeling in Atherosclerosis

Abstract

Background: Despite advances in lipid-lowering and anti-inflammatory therapies, pharmacological strategies that act directly within established atherosclerotic lesions to suppress plaque progression remain limited. We recently developed a monocyte-mimetic nanoparticle (MoNP) platform that selectively targets inflamed endothelium and delivers Verteporfin (VP), termed MoNP-VP, to suppress YAP/TAZ-associated endothelial activation and plaque development. Here, we extend this biomimetic nanotherapy by defining the pharmacological effects of MoNP-VP within atherosclerotic vessels and evaluating its therapeutic efficacy in pre-existing plaques under distinct lipid burden. Methods: MoNP-VP were formulated by encapsulating VP in polymeric cores followed by cloaking with mouse monocyte membranes. Partial ligation was performed in ApoE-deficient mice, and single-cell RNA sequencing was used to define pharmacodynamic responses in carotid lesions. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function was induced in wild-type mice to generate pre-existing aortic lesions, followed by continued high-fat-diet or switching to chow to evaluate MoNP-VP efficacy under persistent hyperlipidemia and lipid-lowering conditions. Results: Single-cell analysis revealed that MoNP-VP remodeled the plaque microenvironment in carotid arteries, selectively reducing foamy macrophage populations while enriching vascular stromal populations associated with fibrotic remodeling. In mice with pre-existing aortic plaques, MoNP-VP suppressed lesion progression and reduced macrophage content under persistent hyperlipidemia. Following diet-induced lipid lowering, MoNP-VP further reduced macrophage accumulation despite no significant change in plaque size. Across both settings, MoNP-VP increased fibroblast-like cell populations and collagen deposition accompanied by activation of TGF{beta} signaling, features consistent with a more stable plaque. Importantly, repeated MoNP-VP administration was well tolerated and elicited no overt systemic toxicity. Conclusion: These findings bridge mechanistic insight and therapeutic efficacy in pre-established plaques by demonstrating that MoNP-VP remodels the inflammatory plaque microenvironment and promotes lesion stabilization, supporting its translational potential as a precision nanotherapy for atherosclerosis.