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

Sezin Aday¹, Inbal Hazan-Halevy², Aranzazu Chamorro-Jorganes³

¹Bristol Heart Institute, University of Bristol, Bristol BS2 8ED, UK; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy

|March 21, 2021

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.

Insights

Researchers identified the let-7 miRNA family in proangiogenic small extracellular vesicles (sEVs). They developed artificial exosomes (AEs) using lipid nanoparticles and let-7b-5p, demonstrating enhanced endothelial cell survival and angiogenesis in vitro and in vivo.

Area of Science:

Biotechnology
Molecular Biology
Nanomedicine

Background:

Small extracellular vesicles (sEVs) derived from stem cells promote angiogenesis, a process crucial for tissue repair and development.
MicroRNAs (miRNAs) within sEVs are key regulators of gene expression and contribute to their proangiogenic effects.
Lipid nanoparticles (LNPs) are a validated platform for RNA therapeutics, offering potential for engineered delivery systems.

Purpose of the Study:

To identify specific miRNAs responsible for the proangiogenic activity of sEVs.
To engineer bioinspired artificial exosomes (AEs) by encapsulating proangiogenic miRNAs within LNPs.
To evaluate the therapeutic potential of these AEs in promoting angiogenesis and endothelial cell function.

Main Methods:

Analysis of miRNA expression profiles from proangiogenic sEVs sourced from various human tissues and cell types.
Development of LNP-based AEs loaded with specific miRNAs, including hsa-let-7b-5p and a control miRNA.
In vitro assays assessing cytotoxicity, miRNA transfer, endothelial cell (EC) survival under hypoxia, and angiogenic potential.
In vivo studies to validate the angiogenic capacity of the developed AEs.

Main Results:

The let-7 miRNA family was identified as a common proangiogenic signature in sEVs from diverse sources.
Bioengineered let-7b-5p-loaded AEs showed no toxicity and effectively transferred functional miRNA to recipient ECs.
AEs significantly enhanced EC survival under hypoxic conditions and promoted angiogenesis in both in vitro and in vivo models.

Conclusions:

The let-7 family of miRNAs plays a critical role in mediating the proangiogenic effects of sEVs.
Bioinspired AEs, combining LNPs with proangiogenic miRNAs, represent a promising nanomedicine platform.
These AEs hold potential for therapeutic applications in treating ischemic diseases by promoting neovascularization.

Read full analysis

Keywords:

angiogenesis endothelial cells extracellular vesicles let-7b-5p microRNAs nanomedicine

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