Blebbisomes: Redefining the extracellular vesicles landscape through organelle-rich extracellular entities

Extracellular vesicles (EVs) are key mediators of intercellular communication, transferring bioactive molecules that influence physiological and pathological processes. Traditionally classified as exosomes, microvesicles, or apoptotic bodies, EVs are now recognised to include a broader spectrum of structures with distinct origins and functions. Among these, blebbisomes have emerged as a newly identified class of large extracellular vesicles (L-EVs) that significantly expand our understanding of EV diversity. Generated through non-apoptotic plasma membrane retraction, blebbisomes are exceptionally large and exhibit complex internal organization, containing intact and functional organelles, including mitochondria, endoplasmic reticulum, Golgi apparatus, and ribosomes, while lacking a nucleus. Unlike conventional EVs, blebbisomes display sustained contractility, metabolic activity, and the ability to both internalize and secrete smaller vesicles, suggesting a semi-autonomous behavior within the extracellular space. In cancer, their enrichment in immune checkpoint proteins indicates a potential role in immune evasion and communication with the tumor microenvironment. Despite their intriguing features, the biology of blebbisomes remains largely unexplored. Key questions concern the molecular mechanisms of their formation, the functional transferability of their organelles, and their physiological significance in vivo. Furthermore, the lack of standardized methods for isolation and characterization limits their translational evaluation. Overall, blebbisomes represent a conceptual and functional frontier in EV research, opening new perspectives on cellular organization, intercellular communication, and cancer biology.