Tumor-derived extracellular vesicles: From biogenesis and molecular composition to translational therapeutics

Extracellular vesicles (EVs) have emerged as vital mediators of cell-to-cell communication in cancer. Tumor-derived EVs (TD-EVs) actively remodel the tumor microenvironment (TME) by transferring a complex cargo of oncogenic proteins, regulatory RNAs, lipids, and metabolites, thereby influencing tumor growth, angiogenesis, metastasis, and immune modulation. This review explains the biogenesis pathways and molecular composition of TD-EVs, highlighting how endosomal sorting complexes, Rab GTPases, tetraspanins, and lipid metabolism collectively determine vesicle release and functional specificity. Comparative analyses of proteomic, transcriptomic, and lipidomic profiles reveal that TD-EVs carry tumor-specific signatures that can serve as non-invasive diagnostic and prognostic biomarkers. Mechanistic insights emphasize the crosstalk between tumor and stromal cells mediated by EVs, which reprogram fibroblasts, immune cells, and endothelial cells toward pro-tumorigenic phenotypes. Advances in EV engineering, encompassing surface modification, cargo loading, and hybrid synthetic vesicle design, have expanded their role as nanocarriers for targeted drug and gene delivery. In addition, EV imaging and tracking innovations such as fluorescence labeling, magnetic resonance-based probes, and bioluminescent reporters enable real-time in vivo visualization and biodistribution analysis. This review critically evaluates emerging preclinical models and early-phase clinical applications of EV-based nanotherapeutics, while explicitly addressing the rigorous translational bottlenecks, such as Good Manufacturing Practice (GMP) scalability, pharmacokinetic unpredictability, and inherent biological heterogeneity, that currently impede their progression into routine clinical use. The findings position TD-EVs as both critical regulators of tumor biology and versatile platforms for precision cancer therapy, bridging molecular oncology with next-generation nanomedicine.