Large extracellular vesicles and blebbisomes in cancer: emerging and translational opportunities highlights

Large extracellular vesicles (lEVs), particularly the recently identified blebbisomes, are emerging as critical mediators of tumor progression and intercellular communication. Compared with small vesicles, lEVs exhibit pronounced heterogeneity in size, cargo composition, and mechanisms of biogenesis. While EVs of all sizes can carry proteins, nucleic acids, lipids, and metabolites, lEVs more frequently encapsulate bulky cargos-including intact organelles such as mitochondria-reflecting their size-enabled loading capacity rather than a feature unique to lEVs. These characteristics position lEVs as key regulators of immune responses, metabolic reprogramming, and the establishment of pre-metastatic niches within the tumor microenvironment. Blebbisomes, distinguished by their dynamic membrane behavior, bidirectional cargo transfer, and high expression of immunosuppressive molecules, represent a novel paradigm in extracellular communication. However, challenges persist in defining lEV subtypes, achieving efficient purification and isolation, and accurately tracking their behavior in vivo. This review systematically summarizes recent advances in lEV research in tumor biology, highlights the distinctive functions of blebbisomes, and examines their translational potential in diagnostics and therapy. Key knowledge gaps are identified, including the need for single-vesicle multi-omics, advanced lipidomics, and engineered analytical platforms. We advocate for expanded investigation into lEVs as promising targets and tools in precision oncology.