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Harnessing extracellular vesicle heterogeneity for diagnostic and therapeutic applications

Nature Nanotechnology volume 20, pages 14–25 (2025)Cite this article

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Abstract

Extracellular vesicles (EVs) are diverse nanoparticles with large heterogeneity in size and molecular composition. Although this heterogeneity provides high diagnostic value for liquid biopsy and confers many exploitable functions for therapeutic applications in cancer detection, wound healing and neurodegenerative and cardiovascular diseases, it has also impeded their clinical translation—hence heterogeneity acts as a double-edged sword. Here we review the impact of subpopulation heterogeneity on EV function and identify key cornerstones for addressing heterogeneity in the context of modern analytical platforms with single-particle resolution. We outline concrete steps towards the identification of key active biomolecules that determine EV mechanisms of action across different EV subtypes. We describe how such knowledge could accelerate EV-based therapies and engineering approaches for mimetic artificial nanovesicle formulations. This approach blunts one edge of the sword, leaving only a single razor-sharp edge on which EV heterogeneity can be exploited for therapeutic applications across many diseases.

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Fig. 1: EVs exhibit major heterogeneity that currently limits their effective application in drug delivery.
Fig. 2: Generalized experimental workflow for determining the EV MOA in the context of single-vesicle heterogeneity.
Fig. 3: Engineering ANVs to address long-standing challenges that are associated with EVs.

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Acknowledgements

We acknowledge support from the National Institutes of Health, including R01CA241666, R01EB033389, R01EB034279 and R35GM142788. R.R.M. was supported by F31NS120590. N.L. was supported by a funded training grant program (T32HL007013) of the National Heart, Lung, and Blood Institute. T.H. was supported by an NDSEG Fellowship. A.A. was supported by UC Davis MCB T32. This work was supported in part by the UC Davis Comprehensive Cancer Center’s Women’s Cancer Care & Research (WeCARE) program.

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  1. These authors contributed equally: Randy P. Carney, Rachel R. Mizenko.

Authors and Affiliations

  1. Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA

    Randy P. Carney, Rachel R. Mizenko, Batuhan T. Bozkurt, Neona Lowe, Tanner Henson, Alessandra Arizzi, Aijun Wang, Cheemeng Tan & Steven C. George

  2. Center for Surgical Bioengineering, Department of Surgery, University of California, Davis, School of Medicine, Sacramento, CA, USA

    Tanner Henson, Aijun Wang & Steven C. George

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Contributions

R.P.C and R.R.M. wrote the paper and prepared the figures. R.P.C., R.R.M., A.W., C.T. and S.C.G. conceptualized the work. B.T.B., N.L., T.H., A.A., A.W., C.T. and S.C.G. draughted sections of the paper and edited them. N.L. and R.R.M. performed experiments.

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Carney, R.P., Mizenko, R.R., Bozkurt, B.T. et al. Harnessing extracellular vesicle heterogeneity for diagnostic and therapeutic applications. Nat. Nanotechnol. 20, 14–25 (2025). https://doi.org/10.1038/s41565-024-01774-3

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