Small extracellular vesicles proteome reveals persistent inflammatory and coagulopathic dysregulation in long-COVID.

Overview

1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kansas City, KS, United States
2. Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, United States

Abstract

Background: Post-acute sequelae of SARS-CoV-2 (PASC) or Long-COVID affects millions and remains mechanistically undefined due to its heterogeneous clinical presentation. Identifying robust biological signatures is essential for understanding disease mechanisms and improving diagnosis. Here, we investigated the protein cargo of plasma-derived small extracellular vesicles (SEVs) from PASC-positive and PASC-negative individuals to identify EV-linked biomarkers of Long-COVID.

Methods: SEVs were isolated from EDTA plasma of PASC-positive (n=20) and PASC-negative (n=11) individuals using size-exclusion chromatography. SEV protein cargo was profiled across more than 5400 proteins using the Olink Explore HT platform.

Results: PASC-positive patients commonly reported fatigue, shortness of breath, brain fog, sleep disruption, and mood changes. Proteomic analysis revealed 269 significantly dysregulated proteins, including 84 upregulated and 21 downregulated, with a fold change >2 in PASC. These differentially altered proteins were enriched in pathways related to coagulation, inflammation, apoptosis, fibrosis, extracellular matrix remodeling, mitochondrial dynamics, and immune activation. PASC-positive SEVs showed persistent increases in FN1, HCF-H, HGF, and IL-17RA, proteins previously dysregulated in acute COVID-19. These markers showed greater differences in SEVs than in matched plasma, particularly HGF and IL-17RA, which were significantly altered in SEVs but not in plasma.

Conclusion: Proteomic alterations in SEVs from PASC patients highlight the inflammatory, thrombotic, and neurobiological dysregulation, underscoring the potential of SEVs as biomarkers and mechanistic drivers of long COVID.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• zenodo:21283519 — at Zenodo; found in “Data availability statement”

Data availability statement

Original datasets are available in a publicly accessible repository: This data can be found here: https://doi.org/10.5281/zenodo.21283519.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 6 authors, 5 keywords, 13 MeSH terms, 2 funders, 60 references.

Cite

This paper

Chandran, S., Chen, L., Ram, A. K., Spikes, L., Chalise, P., & Dhillon, N. K. (2026). Small extracellular vesicles proteome reveals persistent inflammatory and coagulopathic dysregulation in long-COVID. Frontiers in immunology, 17, 1805159. https://doi.org/10.3389/fimmu.2026.1805159

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