Biomimetic Platelet Membrane-Based Polyphenol–CeO2 Nanozyme Complex: A Broad-Spectrum Antioxidative System for Comprehensive Atherosclerosis Treatment

Atherosclerosis (AS) is a chronic cardiovascular disease characterized by the accumulation of excess lipids within arterial walls. Since oxidative stress is one of the key drivers in its pathogenesis, antioxidative therapy serves as a promising strategy for AS treatment. Despite the potent antioxidant properties of polyphenolic salvianic acid A (SAA) and salvianolic acid B (SAB), clinical application is limited by their short half-life, insufficient target selectivity, and poor chemical stability. To overcome these limitations, we developed a biomimetic platelet membrane-coated polyphenol-cerium dioxide nanozyme complex (SS-CeO2@PLTM) as a broad-spectrum antioxidative system for comprehensive AS treatment. The SS-CeO2@PLTM was constructed by conjugating SAA and SAB on the surface of cerium dioxide via a one-pot method, followed by surface coating with a biomimetic platelet membrane. Systematic characterization using UV-vis spectroscopy, Fourier transform infrared (FT-IR), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy-energy dispersive X-ray spectroscopy (TEM-EDS) elemental mapping analysis, Forster resonance energy transfer (FRET), molecular simulations, and pH-responsive release assays validated the successful synthesis and pH-responsive drug release behavior of SS-CeO2@PLTM. It was also found that SS-CeO2@PLTM exhibited broad-spectrum antioxidant activities, effectively scavenging superoxide anions, DPPH, H2O2, and intracellular reactive oxygen species (ROS) while enhancing hepatic SOD and GSH activities. Further cellular uptake and in vivo targeting assays confirmed their specific targeting for atherosclerotic plaques. SS-CeO2@PLTM demonstrated great efficiency in attenuating oxidative stress, inhibiting lipid uptake and lipid accumulation, mediating cholesterol efflux, and inhibiting inflammatory factor (IL-1β, IL-6, and TNF-α) secretion in RAW264.7 cells. We also found that SS-CeO2@PLTM exhibited improved lipid metabolism and diminished plaque area in apoE-/- mice via attenuating oxidative stress and NF-κB-mediated inflammation. Furthermore, biosafety was verified via hemolysis and in vivo safety tests. This study is the first to reveal the superior efficacy of the PLTM-based nanozyme complex in targeted AS therapy, offering a paradigm shift for multifactorial cardiovascular disease management.