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

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 α-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.