Electric fields trigger ceramide-dependent budding of exosome vesicles into multivesicular endosomes and boost the generation of exosomes

Huang, S.; Chen, L.; Sun, C.; Zhang, J.; Chen, T.; Cao, Y.; Song, Q.; Xu, X.; Tan, X.; Wu, J.; Chen, G.; Zhao, M.; Yang, J.; Zhang, Y.

doi:10.1101/2025.06.25.661423

bioRxiv · 10.1101/2025.06.25.661423

Electric fields trigger ceramide-dependent budding of exosome vesicles into multivesicular endosomes and boost the generation of exosomes

Huang, S.·Chen, L.·Sun, C.·Zhang, J.·Chen, T.·Cao, Y.·Song, Q.·Xu, X.·Tan, X.·Wu, J.·Chen, G.·Zhao, M.·Yang, J.·Zhang, Y.

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Abstract

Exosomes hold immense therapeutic and diagnostic potential, yet their clinical translation remains constrained by low yields. Physiological electric fields (EFs), naturally occurring during wound healing and embryo development, have unexplored roles in exosome biogenesis. Here, we demonstrate that physiological-strength EFs (Direct Current, 50-200 mV/mm) dramatically enhance cellular exosome secretion, achieving a nearly 100-fold increase in a strength-dependent manner. Mechanistically, EFs augmented intraluminal vesicle formation within multivesicular bodies. We proposed a novel EF-driven membrane electroassembly and vesiculogenesis hypothesis and tested it using giant plasma membrane vesicles. We reconstructed EF-induced membrane remodeling and observed EFs driving inward budding of nanoscale exosome-like vesicles. Notably, alternating current EFs (50-400 Hz) exhibited significantly diminished efficacy compared to direct current EFs, highlighting membrane electropolarization-dependent modulation. Pharmacological inhibition of the lipid raft and ceramide almost abolishes EF-induced exosome secretion. Inhibition of the PI3K partially attenuated EF-triggered exosome release. Our findings not only unveil EFs as a potent physiological regulator of exosome secretion but also establish a novel, high-yield production strategy leveraging bioelectric cues. Significant statementWe reported that the bodys natural bioelectricity, the faint electric currents in healing wounds and embryo development, can trigger cells to release 100 times more "natural nanoscale vesicle couriers" called exosomes. This pure physical method is far more efficient than current available technologies, paving the way for breakthroughs in cancer early detection, stem cell therapies, and precision medicine. We found that gentle electric fields can "blow" the cell membrane to release exosomes like "soap bubbles". This explains how bioelectricity controls cell communication during development and wound healing. In short, harnessing the bodys hidden "electric language" unlocks a fast and natural way to mass-produce exosomes.

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Huang, S., Chen, L., Sun, C., Zhang, J., Chen, T., Cao, Y., Song, Q., Xu, X., Tan, X., Wu, J., Chen, G., Zhao, M., Yang, J., Zhang, Y.. 2025-06-27. Electric fields trigger ceramide-dependent budding of exosome vesicles into multivesicular endosomes and boost the generation of exosomes. https://doi.org/10.1101/2025.06.25.661423

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