Coronary heart disease (CHD) accounts for one-third of deaths in the United States, with an annual economic burden exceeding $400 billion. Elevated plasma levels of low-density lipoprotein-cholesterol (LDL-C) is a major risk factor for CHD, through its promotion of atherosclerosis. Mutations in the LDL receptor (LDLR) are causal for familial hypercholesterolemia, inciting the Ldlr-/- murine model for atherosclerosis studies. Despite >3,000 reports using this model, the technical challenge of low volume blood draws from mice, on top of the limited detection range in plasma, have impeded efforts to identify circulating disease drivers. The recent advent of nanoparticle-dependent biofluid proteomics has enabled more sensitive monitoring of mouse tissue-associated disease drivers in plasma, offering insights into their relevance to human atherosclerosis.