Copper-Doped Prussian Blue Nanozymes With Hyaluronic Acid-Mediated Targeting Alleviate Oxidative Stress and Regulate Cholesterol Handling for Atherosclerosis Therapy.
Ou Jianliang J, Ji Ruihua R, Zang Qinglu Q, Wang Mingkang M et al.
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.