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

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

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


Authors

Sezin Aday

Inbal 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

Paolo Madeddu

Andrew V. Benest

Dan Peer

Costanza Emanueli



Contributors

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.

Journal Article Type Article
Acceptance Date Mar 15, 2021
Online Publication Date Mar 18, 2021
Publication Date Jul 7, 2021
Deposit Date Apr 7, 2021
Publicly Available Date Apr 8, 2021
Journal Molecular Therapy
Print ISSN 1525-0016
Electronic ISSN 1525-0024
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 29
Issue 7
Pages 2239-2252
DOI https://doi.org/10.1016/j.ymthe.2021.03.015
Keywords Molecular Medicine; Genetics; Molecular Biology; Pharmacology; Drug Discovery
Public URL https://nottingham-repository.worktribe.com/output/5435519
Publisher URL https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(21)00144-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1525001621001441%3Fshowall%3Dtrue
Related Public URLs https://www.sciencedirect.com/science/article/pii/S1525001621001441

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