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.