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

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. Exosomes have huge potential for drug delivery, but drug loading can be difficult. Here, the authors report on fusogenic lipid nanoparticles which, when mixed with exosomes rapidly fuse, non-destructively loading large drugs without compromising exosome biological functions, and demonstrate neurological application.