Triglyceride-Rich Conditions Reshape the Protein Corona and Alter Nanobio Interactions

Exposure of nanoparticles (NPs) to biological fluids inevitably results in rapid surface coating by biomolecules, mainly proteins, forming what is commonly termed the protein corona (PC). The PC confers a transformed biological identity to NPs that governs their interaction with physiological systems and influences the pharmacological profile. However, the role of blood metabolites in regulating PC and subsequent nanobio interaction remains undefined. In this study, we examine the impact of elevated triglyceride (TG) levels, clinically termed hypertriglyceridemia, on PC modulation and its related physiological response and pharmacokinetics. We observe that the elevated TG levels differentially regulate PC formation by promoting the adsorption affinity of specific proteins to NPs. The TG-rich PC induces a robust immune response in macrophages by stimulating the release of pro-inflammatory cytokines compared to normal-PC. <i>In vivo</i> experiments reveal that relative to normal mice, NPs in hypertriglyceridemic (HTG) mice show more accumulation and sequestration in the liver and spleen. Furthermore, PC formed in HTG mouse serum shows higher uptake in macrophages and hepatocytes than PC formed in normal mouse serum. Finally, the proteomic analysis reveals distinct disparities in protein adsorption patterns: Lipoproteins are more dominant in HTG-PC, whereas immunoglobulins and complement proteins are more prevalent with normal-PC. Overall, this work offers important insights into the predictive role of disease-related metabolites on the modulating PC and nanobio interaction, aiding in the rational design of nanomedicine.