Exosome-based liquid biopsy for rare and complex diseases

Exosomes, a class of nano-sized extracellular vesicles secreted by virtually all cell types, have emerged as powerful mediators of intercellular communication and promising tools for biomarker discovery. Rich in proteins, lipids, nucleic acids, and metabolites that reflect the physiological and pathological status of their cells of origin, exosomes offer a stable and biologically informative source of diagnostic content readily accessible from body fluids. Their natural abundance, biocompatibility, and lipid bilayer encapsulation, which protects cargo from enzymatic degradation, make them ideal candidates for minimally invasive liquid biopsy applications. Although exosome-based diagnostics have been widely studied in the field of oncology, this review focuses on their emerging applications in non-tumor diseases in order to provide a differentiated perspective. Specifically, we highlight their diagnostic and prognostic value in rare genetic diseases, infectious diseases, autoimmune disorders, and metabolic syndromes. By shifting the focus away from cancer, we aim to complement and expand the current body of literature, avoiding redundancy while uncovering novel translational opportunities. We first outline the biological principles of exosome biogenesis, molecular cargo loading, and intercellular communication. We then assess current exosome isolation and characterization technologies and critically analyze advances in their clinical translation for non-oncological applications. Key challenges such as sample heterogeneity, methodological inconsistencies, and regulatory limitations are also discussed. Finally, we propose strategic solutions including single-vesicle profiling, artificial intelligence-driven data analysis, and the development of clinically scalable, multiplexed diagnostic platforms. With continued technological innovation and cross-disciplinary collaboration, exosome-based diagnostics are well positioned to reshape the future of non-invasive disease detection and precision medicine beyond oncology.