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

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. 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 significance change in plaque size. Across both settings, MoNP-VP increased fibroblast-like cell populations and collagen deposition accompanied by activation of TGFβ signaling — features consistent with a more stable plaque.

Importantly, repeated MoNP-VP administration was well tolerated and elicited no overt systemic toxicity. 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.