Fusogenic lipid nanoparticles for rapid delivery of large therapeutic molecules to exosomes

Gamsong Son, Jiyoung Song, Jae Chul Park, Hong Nam Kim () and Hojun Kim ()
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Gamsong Son: University of Science and Technology
Jiyoung Song: Korea Institute of Science and Technology (KIST)
Jae Chul Park: Korea Institute of Science and Technology (KIST)
Hong Nam Kim: University of Science and Technology
Hojun Kim: University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Exosomes, as cell-derived lipid nanoparticles, are promising drug carriers because they can traverse challenging physiological barriers such as the blood-brain barrier (BBB). However, a major obstacle in utilizing exosomes as drug carriers is loading large therapeutic molecules without compromising the structural integrity of embedded biomolecules. Here, we introduce a membrane fusion method utilizing fusogenic lipid nanoparticles, cubosomes, to load large molecules into exosomes in a non-destructive manner. When the drug-loaded cubosome and exosome solutions are simply mixed, membrane fusion is completed in just 10 min. Our method effectively loads doxorubicin and immunoglobulin G into exosomes. Moreover, even the most challenging molecule—mRNA—is loaded with nearly 100% efficiency, demonstrating the versatility of our approach. In terms of biological behavior, the resulting hybrid exosomes preserve the functional behavior of exosomes in BBB uptake and penetration. Surprisingly, controlling exosome-to-cubosome ratios allows precise control over BBB uptake and transport. Furthermore, these hybrid exosomes retain cell-specific delivery properties, preserving the targeted delivery functions dictated by their exosomal origin. This study demonstrates the feasibility of a mix-and-load method for rapid and efficient drug loading into exosomes, with significant potential for the treatment of neurological diseases.

Date: 2025
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DOI: 10.1038/s41467-025-59489-5

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