Ligand-Mediated Proteome Remodeling Shapes Nanoparticle Protein Corona Composition for Deep Plasma Profiling

The human plasma proteome contains extensive diagnostic information but remains difficult to interrogate because protein concentrations span more than ten orders of magnitude, with highly abundant proteins such as albumin masking low-abundance biomarkers. Nanoparticle (NP) enrichment strategies partially address this limitation, but their analytical depth is still constrained the incorporation of albumin and other highly abundant proteins within the protein corona. Here we show that the NP protein corona can be rationally reprogrammed by pre-incubating plasma with a chemically diverse panel of ligands designed to bind albumin, attenuate its interaction with NPs, and promote enrichment of lower-abundance proteins. Molecular docking and structural analyses demonstrate that these ligands induce allosteric conformational changes and surface charge redistribution on albumin, thereby reducing its association with the NP surface. Importantly, this strategy is highly tunable, as individual ligands shift protein corona composition toward different broad families of proteins, revealing overall enrichment trends rather than strict selectivity for any single class. Using this approach, we quantified over 6,600 proteins from a single human plasma sample across a curated panel of conditions, substantially exceeding the depth achieved with untreated NP enrichment. These findings establish a versatile chem-bio strategy for ligand-directed protein corona engineering, enabling high-depth plasma proteome profiling and expanding access to low-abundance proteins and candidate biomarkers across human diseases.