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Nawaz M, Tangruksa B, Heydarkhan-Hagvall S, Kohl F, Garibotti HG, Jing Y, Payandeh Z, Reyahi A, Jennbacken K, Wiseman J, Hultin L, Lindfors L, Synnergren J, Valadi H
J Extracell Vesicles 15 (6) e70324 [2026-06-00; online 2026-06-11]
Efficient and specific delivery of mRNA to target tissues is critical for maximising therapeutic benefits while minimising off-target effects and systemic toxicity. Systemic administration of mRNA using lipid nanoparticles (LNPs) or extracellular vesicles (EVs) typically leads to predominant accumulation in the liver. We hypothesised that cardiac-specific EVs could promote enhanced relative cardiac enrichment of delivered mRNA compared with non-cardiac EVs or LNPs. In mice, intravenous administration of cardiac progenitor cell-derived EVs (CPC-EVs) achieved the greatest relative cardiac selectivity of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) to the heart, with reduced liver accumulation relative 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 localised and limited cytokine activation, suggesting a more favourable safety profile. Furthermore, direct intramyocardial injection of CPC-EVs not only led to efficient mRNA uptake by cardiac tissue and robust VEGF-A protein expression, but also minimal transcriptomic perturbation in the cardiac tissue, 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. Together, these findings support CPC-EVs as a promising platform for achieving enhanced cardiac delivery of mRNA, with reduced liver accumulation, limited off-target transcriptomic perturbation, a more selective cytokine response, and enhanced angiogenic activity in ex vivo assays.
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 42275464
DOI 10.1002/jev2.70324
Crossref 10.1002/jev2.70324