Deep Profiles

Researchers have demonstrated that adding small molecules to plasma can significantly expand the detection of low-abundance proteins, addressing a major challenge in plasma proteomics. The research, published in Nature Communications, reveals that small molecule-induced modulation of protein coronas on nanoparticles boosts proteome coverage, aiding biomarker discovery and disease monitoring.

Plasma proteomics often struggles with detecting low-abundance proteins because of the dominance of high-abundance ones like albumin, which comprise 85 percent of plasma protein mass. This study explored how small molecules, including phosphatidylcholine (PtdChos), glucose, and triglycerides, influence the protein corona – a layer of proteins adsorbed on nanoparticle surfaces. By modifying plasma samples with these molecules, researchers achieved an 8.25-fold increase in the number of proteins detected compared with plasma alone.

Using polystyrene nanoparticles, the team quantified 1,793 unique proteins through liquid chromatography-mass spectrometry (LC-MS/MS), far surpassing the 218 proteins detected in untreated plasma. Remarkably, PtdChos alone enabled the identification of 897 proteins, including low-abundance ones, by selectively reducing albumin and other high-abundance proteins in the corona.

The study also showed that the addition of PtdChos improved proteoform quantification by enriching proteins linked to diseases like cardiovascular and neurodegenerative disorders.

Molecular dynamics simulations further revealed that PtdChos interacts with albumin through hydrophobic interactions and hydrogen bonds, reducing its representation in the corona. This strategy eliminates the need for costly and labor-intensive albumin depletion kits, streamlining proteomics workflows.

The findings have broad implications for biomarker discovery and personalized medicine. By enabling deeper plasma proteome profiling, the approach could uncover novel biomarkers and improve early disease diagnosis. Future studies aim to validate the method across diverse patient cohorts, paving the way for its clinical adoption in precision diagnostics.