Serum Lipids Remodel the Biomolecular Corona to Direct Nanoparticle Biodistribution

Abstract Biomolecular corona (BC) governs nanoparticle (NP) interactions with biological systems. While the role of proteins in BC regulation is well recognized, the contribution of serum lipids remains largely unexplored. Here, silica magnetic NPs were incubated with normal or hyperlipidemic serum to form BC@NPs, followed by lipidomic and proteomic characterization using LC-MS/MS. Their cellular uptake, biodistribution, and hepatic clearance were subsequently evaluated. Hyperlipidemia profoundly remodeled BC composition, leading to reduced overall protein adsorption while enrichment of cholesterol, triglycerides, and apolipoproteins, particularly APOB, indicative competitive lipid-protein adsorption at the NP surface. This disease-associated BC remodeling enhanced macrophage uptake through LDL receptor–mediated endocytosis and lipid raft-dependent pathways, thereby leading to increased hepatic accumulation via facilitating the uptake by Kupffer cells and hepatocytes. By elucidating the interplay between lipids and proteins in BC formation, this work reveals a previously underappreciated role of serum lipids in regulating NP-bio interactions, especially in lipid-associated diseases.