Lipid Nanoparticles Deliver the Therapeutic VEGFA mRNA In Vitro and In Vivo and Transform Extracellular Vesicles for Their Functional Extensions.

Autor: Nawaz M; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41346, Sweden., Heydarkhan-Hagvall S; BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden.; Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, SE-54128, Sweden., Tangruksa B; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41346, Sweden.; Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, SE-54128, Sweden., González-King Garibotti H; BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Jing Y; Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Maugeri M; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41346, Sweden.; Safety Innovations, Clinical Pharmacology and Safety Sciences, R&D AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Kohl F; BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden.; Department of Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Stockholm, 17177, Sweden., Hultin L; BioPharmaceuticals R&D, Clinical Pharmacology and Safety Science, Imaging and Data Analytics, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Reyahi A; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41346, Sweden., Camponeschi A; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41346, Sweden., Kull B; BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Christoffersson J; BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden.; Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, SE-54128, Sweden., Grimsholm O; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41346, Sweden.; Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, 1090, Austria., Jennbacken K; BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Sundqvist M; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41346, Sweden., Wiseman J; BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Bidar AW; BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Lindfors L; Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, 43183, Sweden., Synnergren J; Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, SE-54128, Sweden.; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41345, Sweden., Valadi H; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41346, Sweden.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2023 Apr; Vol. 10 (12), pp. e2206187. Date of Electronic Publication: 2023 Feb 19.
DOI: 10.1002/advs.202206187
Abstrakt: 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 mRNA differently than LNPs.
(© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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