Bioinspired artificial exosomes based on lipid nanoparticles carrying let-7b-5p promote angiogenesis in vitro and in vivo

Paolo R Madeddu, Costanza Emanueli, Sezin Aday, Hazan-Halevy , Aranzazu Chamorro-Jorganes, Maryam Anwar, Meir Goldsmith, Nicholas Beazley-Long, Susmita Sahoo, Navneet Dogra, Walid Sweaad, Francesco Catapano, Sho Ozaki-Tan, Gianni D Angelini, Andrew Benest, Dan Peer

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)
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Abstract

MicroRNAs (miRNAs) regulate gene expression by post-transcriptional inhibition of target genes. Proangiogenic small extracellular vesicles (sEVs; popularly identified with the name "exosomes") with a composite cargo of miRNAs are secreted by cultured stem cells and present in human biological fluids. Lipid nanoparticles (LNPs) represent an advanced platform for clinically approved delivery of RNA therapeutics. In this study, we aimed to (1) identify the miRNAs responsible for sEV-induced angiogenesis; (2) develop the prototype of bioinspired "artificial exosomes" (AEs) combining LNPs with a proangiogenic miRNA, and (3) validate the angiogenic potential of the bioinspired AEs. We previously reported that human sEVs from bone marrow (BM)-CD34+ cells and pericardial fluid (PF) are proangiogenic. Here, we have shown that sEVs secreted from saphenous vein pericytes and BM mesenchymal stem cells also promote angiogenesis. Analysis of miRNA datasets available in-house or datamined from GEO identified the let-7 family as common miRNA signature of the proangiogenic sEVs. LNPs with either hsa-let-7b-5p or cyanine 5 (Cy5)-conjugated Caenorhabditis elegans miR-39 (Cy5-cel-miR-39; control miRNA) were prepared using microfluidic micromixing. let-7b-5p-AEs did not cause toxicity and transferred functionally active let-7b-5p to recipient endothelial cells (ECs). let-7b-AEs also improved EC survival under hypoxia and angiogenesis in vitro and in vivo. Bioinspired proangiogenic AEs could be further developed into innovative nanomedicine products targeting ischemic diseases.
Original languageEnglish
Pages (from-to)2239-2252
Number of pages14
JournalMol Ther
Volume29
Issue number7
Early online date18 Mar 2021
DOIs
Publication statusPublished - 7 Jul 2021

Bibliographical note

Funding Information:
We acknowledge the help of Dr. Andrew Herman from the Flow Cytometry Facility of University of Bristol, Valeria Alvino (University of Bristol) in the collection and preparation of human saphenous vein pericytes, and Parul Dixit (Imperial College London) for part of the Matrigel plug analyses. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care. For this study, C.E. was supported by the British Heart Foundation (BHF) Centre of Vascular Regeneration-2, a BHF Chair award (CH/15/1/31199), the Leducq Foundation Transatlantic Network of Excellence in Vascular microRNAs, and a BHF project (PG/11/67/29067). This study was also funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. D.P. thanks the Lewis Trust Family for its generous support and the Dotan Hematological Malignancies Fund at Tel Aviv University. A.V.B. is supported by a BHF project grant (PG/18/31/33759) and the Royal Society (RGS\R1\191221). S.A. acknowledges the scholarship from BHF (SS/CH/15/1/31199). S.A. designed and performed experiments, analyzed data, and wrote the manuscript. I.H.-H. A.C.-J. M.A. M.G. N.B.-L. N.D. W.S. F.C. and S.O.-T. performed experiments and analyzed data. G.D.A. and P.M. collected clinical samples under ethical approval, revised the manuscript, and obtained funds for the research. S.S. and A.V.B. analyzed data and revised the manuscript. D.P. and C.E. designed the study and the experiments, wrote the manuscript, and obtained funds for the research. All authors approved the final manuscript. The authors declare no competing interests.

Funding Information:
We acknowledge the help of Dr. Andrew Herman from the Flow Cytometry Facility of University of Bristol, Valeria Alvino (University of Bristol) in the collection and preparation of human saphenous vein pericytes, and Parul Dixit (Imperial College London) for part of the Matrigel plug analyses. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care. For this study, C.E. was supported by the British Heart Foundation (BHF) Centre of Vascular Regeneration-2, a BHF Chair award ( CH/15/1/31199 ), the Leducq Foundation Transatlantic Network of Excellence in Vascular microRNAs, and a BHF project ( PG/11/67/29067 ). This study was also funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol . D.P. thanks the Lewis Trust Family for its generous support and the Dotan Hematological Malignancies Fund at Tel Aviv University . A.V.B. is supported by a BHF project grant ( PG/18/31/33759 ) and the Royal Society ( RGS\R1\191221 ). S.A. acknowledges the scholarship from BHF ( SS/CH/15/1/31199 ).

Publisher Copyright:
© 2021 The Authors

Structured keywords

  • Bristol Heart Institute

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