Exercise-induced extracellular vesicles and their protective role against diabetes

<p dir="ltr">Exercise is known for the positive effects on metabolic diseases, partly because of the release of circulating extracellular vesicles (EVs) that mediate intercellular communication and organ crosstalk. In this thesis, we explored the molecular composition and biofunction of exercise-induced EVs, focusing on their role in health benefits and pancreatic B -cell protection. At same time, we modified and engineered EVs to develop an efficient cellular delivery platform.</p><p dir="ltr">In study I, we compared the systemic effects of circulating EVs induced by continuous aerobic training (CAT) and high-intensity interval training (HIIT) in healthy volunteers. Proteomic and miRNA profiling revealed that EVs from both two types of exercise modalities regulate neuronal signaling, autophagy, and cell fate, while CAT preferentially modulates cognitive function and substrate metabolism, and HIIT is associated with organ growth, cardiac function, and insulin signaling. Notably, the miR-379 cluster was specifically upregulated by HIIT, and EVs were traced to multiple tissues including metabolic, immune, and nervous systems, highlighting their role in organ crosstalk.</p><p dir="ltr">Building on these findings, study II investigated the protective effects of exercise induced EVs on pancreatic B -cells. Exercise induced EVs alleviated endoplasmic reticulum stress-induced apoptosis in ß -cells, predominantly through miR-124-5p derived from the central nervous system. These findings reveal a novel brain-to-islet communication axis, providing molecular insight into how exercise improves ß -cell function and suggesting potential therapeutic strategies against diabetes.</p><p dir="ltr">Finally, in study III, we took advantage of the nature of EVs, we modified and programed them to serve as efficient and customizable cellular delivery platforms by DNA nanotechnology. To enable real-time monitoring of EV-mediated miRNA dynamics, we developed a miRNA detection-amplification system (miRDAS) using extracellular vesicle-based spherical nucleic acids (EV-SNA). This system rapidly safely internalizes into cells and amplifies target miRNA signals in situ. As a proof- of-concept, miR-124-specific miRDAS was employed to track its expression during neuronal differentiation, demonstrating high sensitivity, specificity, and multiplexing capability.</p><p dir="ltr">Collectively, this thesis provides mechanistic understanding of exercise- induced EVs, highlights their critical role in B -cell health, and introduces advanced tools for monitoring EV-mediated miRNA signaling, offering insights for both basic research and potential therapeutic applications.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Wang, Z</b> .* , Ou, Y *. , Zhu, X., Zhou, Y., Zheng, X., Zhang, M., Li, S., Yang, S. N., Juntti-Berggren, L., Berggren, P. O., & Zheng, X. (2025). Differential Regulation of miRNA and Protein Profiles in Human Plasma-Derived Extracellular Vesicles via Continuous Aerobic and High-Intensity Interval Training. International journal of molecular sciences, 26(3), 1383. <a href="https://doi.org/10.3390/ijms26031383" rel="noreferrer" target="_blank">https://doi.org/10.3390/ijms26031383</a></p><p dir="ltr">II. <b>Wang, Z.</b>*, Zhu, X.*, Zhou, Y., , Shi, Y., , Yang, S. N., Zheng, X.,Berggren, P. O Exercise-induced extracellular vesicles protect against islet ß cell failure and diabetes by delivering miR-124-5p [Manuscript]</p><p dir="ltr">III. <b>Wang, Z.</b>, Zhu, X., Zhou, Y., Zhang, T., Shi, Y., Zheng, X., Yang, S. N., Li, W., & Berggren, P. O. (2025). Target-Mediated EV-SNA Clustering as an Amplifier for In Situ miRNA Imaging in Living Cells. Nano letters, 25(31), 11860-11869. <a href="https://doi.org/10.1021/acs.nanolett.5c02256" rel="noreferrer" target="_blank">https://doi.org/10.1021/acs.nanolett.5c02256</a></p>