Programmable Pentamolecular Cross‐Scale Imaging Reveals the Multiplicative Synergistic Effect of High‐Fat / High‐Salt Diet on Atherosclerosis

ABSTRACT Atherosclerosis, as a lipid‐driven chronic inflammatory disease, exhibits close correlation between its early formation and dietary habits, yet lacks closely associated molecular demonstration mechanisms. To address this, we constructed nanosenors for H ₂ O ₂ , HClO, GSH, and AA, achieving cross‐scale fluorescence imaging at cellular, tissue, and in vivo levels for five spectrally distinguishable molecular species through programmed combination of three probe types: oxidative (H ₂ O ₂ , HClO), reductive (GSH, AA), and protein phosphorylation. Using rat models fed with high‐fat, high‐salt, or combined diets, our cross‐scale imaging of oxidative/reductive substances and phosphorylated proteins revealed that both high‐fat and high‐salt diets independently induce redox imbalance in vasculature and organs while significantly elevating protein phosphorylation levels. Notably, the combined high‐fat/high‐salt group demonstrated oxidative stress and protein phosphorylation levels exceeding the additive effects of individual diets (“1+1>2” synergy), unveiling their cooperative acceleration of atherosclerotic progression. This finding provides crucial experimental evidence for understanding the multifactorial synergistic mechanisms whereby lifestyle factors exacerbate oxidative stress and protein phosphorylation in atherosclerosis pathogenesis.