【Paper】Science Advances

This research article was compiled by Ph.D. candidate Mr. Kawaguchi, Assistant Professor Dr. Ajiri, and Ms. Mitsuya. By combining an EV-specific genetic reporter system incorporating the dCas9/gRNA platform with in vivo tracking using bioluminescent and fluorescently labeled extracellular vesicles (EVs), the study demonstrates that circulating and distal organ–derived EVs can pass through the glomerular filtration barrier and be excreted into urine, thereby establishing the potential of urinary EVs as a biomarker platform reflecting systemic diseases.

Paper overview
Extracellular vesicles (EVs) present in urine have attracted considerable attention as noninvasive biomarkers reflecting not only renal diseases but also systemic conditions such as cancer and inflammatory disorders. However, the origin of urinary EVs has long been debated, with most thought to arise primarily from renal and urinary tract epithelial cells. Direct evidence demonstrating whether circulating or distal organ–derived EVs can traverse the glomerular filtration barrier and be excreted into urine has been limited. In this study, we employed two complementary approaches: (1) an EV-specific in vivo genetic reporter system incorporating the dCas9/gRNA platform, and (2) a visualization-based in vivo tracking system using bioluminescent and fluorescently labeled EVs, enabling multifaceted analysis of EV biodistribution and renal excretion pathways. In the former approach, we established a system in which gRNA packaged within EVs induces dCas9-dependent reporter activation in recipient cells, thereby allowing specific detection of EV-derived molecular transfer into cells. In the latter approach, the biodistribution of labeled EVs, their accumulation in the kidney, and their appearance in urine were visualized in real time. Through these independent tracking strategies, we clearly demonstrated that EVs below a certain size threshold can pass through the glomerular filtration barrier and ultimately be excreted into urine. Notably, EV size and surface properties were found to substantially influence filtration efficiency, suggesting that the glomerulus exhibits selective permeability even for nanoscale vesicles. Furthermore, using tumor cell–derived EV models, we confirmed that cancer-derived EVs travel from the circulation to the kidney and subsequently appear in urine, providing direct evidence that urinary EVs can reflect systemic biological information. Taken together, this study integrates multiple in vivo tracking technologies to substantiate the mechanism by which circulating and distal organ–derived EVs undergo glomerular routing and urinary excretion. These findings provide a critical theoretical foundation for the development of urine-based liquid biopsy technologies enabling noninvasive diagnosis and longitudinal monitoring of systemic diseases.

Paper information
Glomerular routing of tumor-derived extracellular vesicles substantiates urinary biopsy
S. Kawaguchi*, T. Ajiri*, R. Mitsuya, R. Tsuchiya, K. Kunitake, Y. Tanaka, T. Yokoyama, K. Sato, Y. Sato, Z. Zhu, K. Chattrairat, Y. Kobayashi, K. Inoue, K. Imaeda, K. Ueno, S. Ryuzaki, A. Kato, Y. Kimura, A. Natsume, R. Kojima* and T. Yasui*
Sci. Adv., 12, eaeb0555 (2026).
https://doi.org/10.1126/sciadv.aeb0555

Science Advances
Science Advances is an open-access, multidisciplinary scientific journal published by the American Association for the Advancement of Science (AAAS). It is an internationally recognized leading journal that publishes cutting-edge research across a broad range of fields in the natural and applied sciences. Covering disciplines from fundamental science and engineering to life sciences, environmental science, and social sciences, the journal aims to rapidly disseminate innovative research with high academic impact to the global scientific community.