Targeted delivery of mRNA to the heart via extracellular vesicles or lipid nanoparticles

Nawaz, M.; Tangruksa, B.; Heydarkhan-Hagvall, S.; Kohl, F.; Gonzalez-King Garibotti, H.; Jing, Y.; Payandeh, Z.; Reyahi, A.; Jennbacken, K.; Wiseman, J.; Hultin, L.; Lindfors, L.; Synnergren, J.; Valadi, H.

doi:10.1101/2025.01.25.634881

bioRxiv · 10.1101/2025.01.25.634881

Targeted delivery of mRNA to the heart via extracellular vesicles or lipid nanoparticles

Nawaz, M.·Tangruksa, B.·Heydarkhan-Hagvall, S.·Kohl, F.·Gonzalez-King Garibotti, H.·Jing, Y.·Payandeh, Z.·Reyahi, A.·Jennbacken, K.·Wiseman, J.·Hultin, L.·Lindfors, L.·Synnergren, J.·Valadi, H.

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Abstract

Targeted mRNA transport plays a crucial role in enhancing the therapeutic efficacy of the molecule, reducing its side effects, and minimizing off-target effects. Systemic administration of mRNA through lipid nanoparticles (LNPs) or extracellular vesicles (EVs) predominantly results in mRNA accumulation in the liver. We hypothesized that cardiac-specific EVs could more effectively target the transport of mRNA to the heart, in comparison to non-cardiac-specific EVs or LNPs. In mice, after intravenous administration, EVs from cardiac progenitor cells (CPC-EVs) were the most efficient to transport the modified mRNA, encoding vascular endothelial growth factor A (VEGF-A), to mouse heart, with minimal liver accumulation compared to non-cardiac-specific EVs or LNPs. Additionally, intracardiac injections of CPC-EVs not only demonstrate that they are the most adapted vehicle for interacting with heart tissue, delivering the mRNA to cells, and inducing maximal VEGF-A protein production, but RNA-seq analyses also revealed their minimal impact on overall gene expression, compared to LNPs or non-cardiac-specific EVs. Furthermore, immunofluorescence staining of CD31 and -SMA, markers of microvascular density, showed increased vessel density in mouse aortic rings following the delivery of VEGF-A mRNA via CPC-EVs. These findings suggest that CPC-EVs are superior in mRNA targeting to heart, communication with cardiac cells, and causing minimal transcriptomic changes during VEGF-A mRNA delivery. Therefore, CPC-EVs could be promising vectors for heart-targeted mRNA delivery, potentially reducing liver accumulation.

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Nawaz, M., Tangruksa, B., Heydarkhan-Hagvall, S., Kohl, F., Gonzalez-King Garibotti, H., Jing, Y., Payandeh, Z., Reyahi, A., Jennbacken, K., Wiseman, J., Hultin, L., Lindfors, L., Synnergren, J., Valadi, H.. 2025-01-26. Targeted delivery of mRNA to the heart via extracellular vesicles or lipid nanoparticles. https://doi.org/10.1101/2025.01.25.634881

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