Blebbisomes are large, organelle-rich extracellular vesicles with cell-like properties

Dennis K Jeppesen ^1,✉,#, Zachary C Sanchez ^2,#, Noah M Kelley ², James B Hayes ², Jessica Ambroise ², Emma N Koory ², Evan Krystofiak ², Nilay Taneja ², Qin Zhang ¹, Matthew M Dungan ³, Olivia L Perkins ², Matthew J Tyska ², Ela W Knapik ^1,2, Kevin M Dean ⁴, Amanda C Doran ³, Robert J Coffey ^1,2, Dylan T Burnette ^2,

Abstract

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.

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Publication History:
Nat Cell Biol. 2025 Feb 21;27(3):438–448. doi: 10.1038/s41556-025-01621-0

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These authors contributed equally: Dennis K. Jeppesen, Zachary C. Sanchez.