Analysis of 515 human proteomes defines plasma extracellular vesicle core composition, corona and coisolated networks

Plasma extracellular vesicles (EVs) are promising liquid biopsy biomarkers, yet their proteomic profiling remains confounded by massive co-isolation. Here, we resolve this heterogeneity through a meta-analysis of 515 human plasma EV proteomes. We demonstrate that the reproducible core proteome is overwhelmingly governed by predictable, surface-charge-driven mass-action that dynamically mirrors synthetic nanoparticle corona formation. By quantitatively decomposing the core isolate against pan-synthetic coronas and agonist-induced platelet EVs, we trace the core isolate to three main mechanistic origins: an electrostatic plasma corona, ex vivo platelet vesiculation and biological macromolecular co-isolates. Crucially, the residual vesicular cargo strongly correlates with thrombin-induced platelet degranulation, indicating that phlebotomy-induced trauma contribute to the bulk signal. We provide a modular atlas that mathematically distinguishes biophysical coronas from these cellular co-isolates, establishing a new framework for interpreting biological origin in plasma EV proteomics.