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Lipid nanoparticles (LNPs) are currently used to transport functional mRNAs, such as COVID-19 mRNA vaccines. The delivery of angiogenic molecules, such as therapeutic VEGF-A mRNA, to ischemic tissues for producing new blood vessels is an emerging strategy for the treatment of cardiovascular diseases. Here, the authors deliver VEGF-A mRNA via LNPs and study stoichiometric quantification of their uptake kinetics and how the transport of exogenous LNP-mRNAs between cells is functionally extended by cells’ own vehicles called extracellular vesicles (EVs). The results show that cellular uptake of LNPs and their mRNA molecules occurs quickly, and that the translation of exogenously delivered mRNA begins immediately. Following the VEGF-A mRNA delivery to cells via LNPs, a fraction of internalized VEGF-A mRNA is secreted via EVs. The overexpressed VEGF-A mRNA is detected in EVs secreted from three different cell types. Additionally, RNA-Seq analysis reveals that as cells’ response to LNP-VEGF-A mRNA treatment, several overexpressed proangiogenic transcripts are packaged into EVs. EVs are further deployed to deliver VEGF-A mRNA in vitro and in vivo. Upon equal amount of VEGF-A mRNA delivery via three EV types or LNPs in vitro, EVs from cardiac progenitor cells are the most efficient in promoting angiogenesis per amount of VEGF-A protein produced. Intravenous administration of luciferase mRNA shows that EVs could distribute translatable mRNA to different organs with the highest amounts of luciferase detected in the liver. Direct injections of VEGF-A mRNA (via EVs or LNPs) into mice heart result in locally produced VEGF-A protein without spillover to liver and circulation. In addition, EVs from cardiac progenitor cells cause minimal production of inflammatory cytokines in cardiac tissue compared with all other treatment types. Collectively, the data demonstrate that LNPs transform EVs as functional extensions to distribute therapeutic mRNA between cells, where EVs deliver this, CC BY 4.0© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.E-mail: hadi.valadi@gu.seThe authors acknowledge the support from the National Genomics Infrastructure in Stockholm funded by Science for Life (SciLife) Laboratory, the Knut and Alice Wallenberg Foundation and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. Moreover, the authors acknowledge Mr. Mario Soriano Navarro at the Responsable Servicio Microscopía Electrónica, Valencia Spain, for technical assistance. This work was supported by grants from the Swedish Foundation of Strategic Research (Stiftelsen för strategisk forskning: SSF) in the Industrial Research Centre, FoRmulaEx - Nucleotide Functional Drug Delivery (Grant ID: IRC15-0065), the Swedish research council (VR, Grant ID: 2020-01316), and the Swedish governmental agency for innovation systems (VINNOVA, Grant ID: 2017-02960). This research was also funded by the Systems Biology Research Centre at the University of Skövde under grants from the Knowledge Foundation (Grant ID: 20160330).