Copper‐Doped Prussian Blue Nanozymes With Hyaluronic Acid‐Mediated Targeting Alleviate Oxidative Stress and Regulate Cholesterol Handling for Atherosclerosis Therapy

ABSTRACT Atherosclerosis is driven by the persistent crosstalk among chronic inflammation, oxidative stress, and lipid dysmetabolism, largely orchestrated by plaque‐resident macrophages. However, therapeutic strategies capable of simultaneously modulating these interconnected pathological processes are still limited. Herein, we developed a hyaluronic acid‐coated, copper‐doped Prussian blue nanozyme (CuPB@HA) as a CD44‐associated plaque‐targeted nanotherapeutic. Guided by transcriptomic evidence of CD44 enrichment in atherosclerotic plaque macrophages, HA was incorporated to enhance lesion targeting and cellular internalization. In ox‐LDL‐stimulated macrophages, CuPB@HA effectively alleviated oxidative stress, suppressed inflammation, and attenuated lipid accumulation. Mechanistically, it reduced CD36‐dependent lipid uptake and increased the expression of cholesterol‐efflux‐related transporters ABCA1 and ABCG1, thereby shifting macrophages away from a pro‐inflammatory phenotype. In vivo, CuPB@HA preferentially accumulated within atherosclerotic lesions of ApoE −/− mice, significantly reducing plaque burden and improving plaque stability‐associated histological features. Collectively, CuPB@HA integrates redox regulation, macrophage lipid‐handling modulation, and inflammation attenuation, highlighting its potential as a targeted therapeutic strategy for atherosclerosis.