Extreme Tolerance of Nanoparticle‐Protein Corona to Ultra‐High Abundance Proteins Enhances the Depth of Serum Proteomics

Abstract The serum nanoparticle‐protein corona (NPC) provides specific disease information, thus opening a new avenue for high‐throughput in‐depth proteomics to facilitate biomarker discovery. Yet, little is known about the interactions between NPs and proteins, and its role in enhanced depth of serum proteomics. Herein, a series of protein spike‐in experiments are conducted to systematically investigate protein depletion and enrichment during NPC formation. Proteomic depth is serum concentration‐dependent, and NPC exhibits powerful tolerance to ultra‐high abundant proteins. In addition, protein‐protein interactions (PPI), especially those involving albumin, play a pivotal role in promoting proteomic depth. Furthermore, a triple‐protein assay is established to interrogate the relationship between protein binding affinity and concentration. NPC formation is a product of balancing binding affinity, concentration, and PPI. Overall, this study elucidates how NPs achieve protein depletion and enrichment for enhanced serum proteomic depth to gain a better understanding of NPC as an essential tool of proteome profiling.