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 remain dominated by albumin adsorption. Here we show that the nanoparticle protein corona can be rationally reprogrammed by pre-incubating plasma with a chemically diverse panel of ligands designed to (i) target specific functional sites on albumin and (ii) reduce its interactions with NPs. Molecular docking and structural analyses demonstrate that these ligands induce allosteric conformational changes and surface charge redistribution on albumin, inhibiting its association with the NP surface. Importantly, this strategy is highly tunable, as different ligands selectively enrich distinct families of low-abundance proteins within the corona. Using this approach, we quantified over 6,500 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 robust detection of ultra-low-abundance proteins and potential biomarkers across human diseases.