Cardiac progenitor cell-derived EVs enhance targeted mRNA delivery to the heart, reducing liver accumulation and systemic inflammation

Efficient and specific mRNA delivery to target tissues is crucial for therapeutic efficacy and minimizing off-target effects. Systemic administration of mRNA, typically via lipid nanoparticles (LNPs) or extracellular vesicles (EVs), predominantly accumulates in the liver. This hepatic tropism limits the therapeutic potential for non-hepatic diseases, particularly cardiac conditions requiring localized gene expression. Current methods often lead to widespread inflammation or lack sufficient tissue specificity, necessitating novel strategies for enhanced cardiac targeting and improved safety profiles.

Researchers investigated cardiac-specific mRNA delivery using cardiac progenitor cell-derived EVs (CPC-EVs), non-cardiac EVs, and LNPs in mice. Modified mRNA encoding vascular endothelial growth factor A (VEGF-A) was administered intravenously. They compared relative cardiac enrichment, liver accumulation, and cytokine profiles across seven organs. Additionally, direct intramyocardial injection of CPC-EVs was performed to assess mRNA uptake, VEGF-A protein expression, and transcriptomic perturbation via RNA-seq. Angiogenic potential was evaluated using ex vivo aortic ring assays.

Intravenous administration of CPC-EVs achieved the greatest relative cardiac selectivity of VEGF-A mRNA in mice, with reduced liver accumulation compared to non-cardiac EVs and LNPs. Cytokine profiling across seven organs revealed that LNP delivery triggered a widespread pro-inflammatory response, whereas CPC-EVs elicited only a localized and limited cytokine activation, suggesting a more favorable safety profile. Furthermore, direct intramyocardial injection of CPC-EVs led to efficient mRNA uptake and robust VEGF-A protein expression in cardiac tissue, with minimal transcriptomic perturbation, as confirmed by RNA-seq. In contrast, LNPs and non-cardiac EVs induced widespread perturbation in the transcriptome of cardiac tissue. Functionally, VEGF-A mRNA delivery via CPC-EVs markedly increased CD31 and α-SMA expression and vessel formation in ex vivo aortic ring assays, confirming enhanced angiogenic potential.