MultifunctionalNanomedicine for Targeted AtherosclerosisTherapy: Activating Plaque Clearance Cascade and Suppressing Inflammation

Atherosclerosis (AS) is a prevalent inflammatory vascular disease characterized by plaque formation, primarily composed of foam cells laden with lipids. Despite lipid-lowering therapies, effective plaque clearance remains challenging due to the overexpression of the CD47 molecule on apoptotic foam cells, inhibiting macrophage-mediated cellular efferocytosis and plaque resolution. Moreover, AS lesions are often associated with severe inflammation and oxidative stress, exacerbating disease progression. Herein, we introduce a multifunctional nanomedicine (CEZP) targeting AS pathogenesis via a “cell efferocytosis–lipid degradation–cholesterol efflux” paradigm, with additional anti-inflammatory properties. CEZP comprises poly(lactic-<i>co</i>-glycolic acid) nanoparticles encapsulated within a metal–organic framework shell coordinated with zinc ions (Zn²⁺) and epigallocatechin gallate (EGCG), enabling CpG encapsulation. Upon intravenous administration, CEZP accumulates at AS plaque sites, facilitating macrophage uptake and orchestrating AS treatment through synergistic mechanisms. CpG enhances cellular efferocytosis, Zn²⁺ promotes intracellular lipid degradation, and EGCG upregulates adenosine 5′-triphosphate-binding cassette transporters for cholesterol efflux while also exhibiting antioxidant and anti-inflammatory effects. <i>In vivo</i> validation confirms CEZP’s ability to stabilize plaques, reduce lipid burden, and modulate the macrophage phenotype. Moreover, CEZP is excreted from the body without safety concerns, offering a low-toxicity nonsurgical strategy for AS plaque eradication.