The blood plasma proteome is a rich reservoir of potential biomarkers that reflect an individual’s health condition. However, the comprehensive identification and quantification of plasma proteins is challenging due to the vast dynamic range of protein concentrations—spanning over 10 orders of magnitude. Traditional methods, such as sample preparation fractionation and enrichment, aim to enhance the detection of low-abundance proteins and peptides, yet often present limitations in detecting rare proteins that are masked by the presence of abundant proteins. A promising frontier technology has been emerging to overcome such limitations: leveraging nanoparticle protein coronae to enrich low-abundance plasma proteins and unveil previously inaccessible layers of the proteome. This Perspective highlights the capabilities of the protein corona technology in enhancing proteome coverage, addresses its current limitations—specifically regarding protein aggregates and extracellular vesicle contaminations—and outlines future directions in proteoform analysis and causal inference.