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Synthetic chemically modified mRNAs (modRNA) encoding vascular endothelial growth factor (VEGF) represents an alternative to gene therapy for the treatment of ischemic cardiovascular injuries. However, novel delivery approaches of modRNA are needed to improve therapeutic efficacy in the diseased setting. We hypothesized that cell-mediated modRNA delivery may enhance the in vivo expression kinetics of VEGF protein thus promoting more potent angiogenic effects. Here, we employed skin fibroblasts as a "proof of concept" to probe the therapeutic potential of a cell-mediated mRNA delivery system in a murine model of critical limb ischemia (CLI). We show that fibroblasts pre-treated with VEGF modRNA have the potential to fully salvage ischemic limbs. Using detailed molecular analysis we reveal that a fibroblast-VEGF modRNA combinatorial treatment significantly reduced tissue necrosis and dramatically improved vascular densities in CLI-injured limbs when compared to control and vehicle groups. Furthermore, fibroblast-delivered VEGF modRNA treatment increased the presence of Pax7+ satellite cells, indicating a possible correlation between VEGF and satellite cell activity. Our study is the first to demonstrate that a cell-mediated modRNA therapy could be an alternative advanced strategy for cardiovascular diseases. Unlabelled Image • Modified mRNAs encoding Vascular Endothelial Growth Factor (VEGF-A) reduces tissue necrosis in a model of CLI/PAD • Human fibroblasts secreting low-dose administration of modified mRNAs improves perfusion following ischemic injury • Cell-mediated protein release from hFbs pre-treated with modified VEGF mRNA results in increased capillary densities and superior neovessel formation in ischemic tissue • Cell-based delivery of VEGF modRNA enhances satellite cell activity effectively promoting skeletal muscle regeneration [ABSTRACT FROM AUTHOR]