Blebbisomes are large, organelle-rich extracellular vesicles with cell-like properties
Cells secrete a large variety of extracellular vesicles (EVs) to engage in cell-to-cell and cell-to-environment intercellular communication. EVs are functionally involved in many physiological and pathological processes by interacting with cells that facilitate transfer of proteins, lipids and genetic information. However, our knowledge of EVs is incomplete. Here we show that cells actively release exceptionally large (up to 20 µm) membrane-enclosed vesicles that exhibit active blebbing behavior, and we, therefore, have termed them blebbisomes. Blebbisomes contain an array of cellular organelles that include functional mitochondria and multivesicular endosomes, yet lack a definable nucleus. We show that blebbisomes can both secrete and internalize exosomes and microvesicles. Blebbisomes are released from normal and cancer cells, can be observed by direct imaging of cancer cells in vivo and are present in normal bone marrow. We demonstrate that cancer-derived blebbisomes contain a plethora of inhibitory immune checkpoint proteins, including PD-L1, PD-L2, B7-H3, VISTA, PVR and HLA-E. These data identify a very large, organelle-containing functional EV that act as cell-autonomous mobile communication centres capable of integrating and responding to signals in the extracellular environment.
Authors
- Dennis K. Jeppesen (ORCID: https://orcid.org/0000-0002-7480-8083)
- Matthew M Dungan (ORCID: https://orcid.org/0000-0002-2989-5982)
- Evan Krystofiak (ORCID: https://orcid.org/0000-0002-0043-6977)
- James B. Hayes (ORCID: https://orcid.org/0000-0002-9321-212X)
- Matthew J. Tyska (ORCID: https://orcid.org/0000-0003-2238-6189)
- Zachary Sanchez (ORCID: https://orcid.org/0000-0001-9075-1577)
- Robert J. Coffey (ORCID: https://orcid.org/0000-0002-2180-3844)
- Nilay Taneja (ORCID: https://orcid.org/0000-0002-9046-0953)
- Amanda C. Doran (ORCID: https://orcid.org/0000-0002-1576-6274)
- Dylan T. Burnette (ORCID: https://orcid.org/0000-0002-2571-7038)
- Emma Koory (ORCID: https://orcid.org/0009-0009-8420-883X)
- Ela W. Knapik (ORCID: https://orcid.org/0000-0002-2977-3619)
- Jérôme Ambroise (ORCID: https://orcid.org/0000-0002-1218-6143)
- Kevin M. Dean (ORCID: https://orcid.org/0000-0003-0839-2320)
- Qin Zhang (ORCID: https://orcid.org/0000-0002-3337-416X)
- Olivia L. Perkins (ORCID: https://orcid.org/0000-0002-6073-305X)
- Noah M. Kelley (ORCID: https://orcid.org/0009-0002-7700-773X)
Institutions
- Vanderbilt University (US)
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1038/s41556-025-01621-0
- Citations
- 45
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 36.27
Funders
- American Heart Association
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- Division of Cancer Epidemiology and Genetics, National Cancer Institute