Hyperlipidemia-Specific Protein Corona Formed on Silver Nanoparticles Aggravates Atherosclerosis by Facilitating Macrophage Lipid Accumulation.

Abstract

Cardiovascular disease continues to be a leading cause of mortality worldwide, but the mechanistic interplay between hypercholesterolemia and environmental pollutants in the progression of atherosclerosis remains poorly understood. This study investigated the role of silver nanoparticles (AgNPs), a typical particulate contaminant, in promoting atherogenic risk under dyslipidemic conditions. Elevated serum cholesterol levels significantly promoted the adsorption of low-molecular-weight hydrophobic proteins to AgNPs. The hyperlipidemia-specific PC facilitated macrophage uptake of AgNPs through lipid-raft-dependent, scavenger receptor-B1-mediated endocytosis, altered intracellular journey to target the endoplasmic reticulum and Golgi apparatus, and exploited Golgi secretory vesicles for exocytosis. Due to dynamic intracellular exchange, the recruitment of chaperones by AgNPs acted as an initiating event to activate endoplasmic reticulum stress (ERS). The <i>in vitro</i> macrophage model showed that AgNPs further triggered M1 polarization and lipid accumulation, ultimately driving foam cell transformation and exacerbating atherogenic risk. In addition, <i>in vivo</i> assays strongly corroborated that AgNPs accelerated atherosclerotic progression in hyperlipidemic mice, which could be reversed by 4-phenylbutyric acid, a chemical chaperone that inhibits ERS. These findings underscore the significant impact of the physiological microenvironment on nano-bio interactions and provide mechanistic insights into the aggravation of cardiovascular diseases by environmental nanoparticles under hypercholesterolemic conditions.