Engineered nanozymes enhance atherosclerosis therapy via inflammation-lipid homeostasis modulation

The pathological process of atherosclerosis (AS) is driven by the complex interplay of dyslipidemia, oxidative stress, and chronic inflammation, wherein the "inflammation-lipid" vicious cycle between macrophages and vascular smooth muscle cells (VSMCs) accelerates plaque progression and rupture. Traditional monotherapies are often insufficient to address these intertwined pathological drivers, underscoring the need for the development of multi-targeted therapeutic strategies. In this context, Prussian blue nanoparticles (PBs) are an ideal candidate for integrated therapy, featuring a hollow mesoporous structure, high photothermal conversion efficiency, and intrinsic enzyme-mimicking activity, providing a multifunctional "all-in-one" scaffold for drug delivery and reactive oxygen species (ROS) scavenging. In this study, we synthesized mesoporous PBs via a hydrothermal method and functionalized their surfaces with polyethyleneimine (PEI) to facilitate drug loading and subsequent modification. The lipid-lowering agent simvastatin (SIM) was encapsulated within the mesopores, followed by the electrostatic assembly of chondroitin sulfate (CS) onto the surface to yield the engineered nanozyme, CS-PEI/PB@SIM (CPPS). This platform achieves precise targeting of CD44 receptors overexpressed on macrophages and VSMCs within the plaque microenvironment. Both in vitro and in vivo experiments demonstrate that CPPS exerts potent multi-enzyme activities that functionally complement PB-mediated photothermal therapy (PTT) to quench ROS and effectively alleviate inflammatory responses. More importantly, this engineered nanozyme restores inflammation-lipid homeostasis, suppresses foam cell formation, and significantly reduces plaque burden in AS model mice. Collectively, our findings suggest that CPPS represents a promising nanotherapeutic intervention for the comprehensive management of AS.