Exosomes as nanocarriers for siRNA delivery: paradigms and challenges

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Abstract

Exosomes are nano-sized vesicles that facilitate intercellular communications through carrying genetic materials and functional biomolecules. Owing to their unique size and structure, exosomes have emerged as a useful tool to overcome the limitations of siRNA delivery. The use of exosomes as siRNA delivery vehicles lacks certain disadvantages of the existing foreign delivery systems such as viruses, polycationic polymers and liposomes, and introduces several advantages including inherent capacity to pass through biological barriers and escape from phagocytosis by the reticuloendothelial system, as well as being biocompatible, non-toxic, and immunologically inert. Different strategies have been employed to harness exosome-based delivery systems, including surface modification with targeting ligands, and using exosome-display technology, virus-modified exosomes, and exosome-mimetic vesicles. The present review provides a capsule summary of the recent advances and current challenges in the field of exosome-mediated siRNA delivery.

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The promises and pitfalls of RNA-interference-based therapeutics.

Daniela Castanotto, John J Rossi (2009)

The discovery that gene expression can be controlled by the Watson-Crick base-pairing of small RNAs with messenger RNAs containing complementary sequence - a process known as RNA interference - has markedly advanced our understanding of eukaryotic gene regulation and function. The ability of short RNA sequences to modulate gene expression has provided a powerful tool with which to study gene function and is set to revolutionize the treatment of disease. Remarkably, despite being just one decade from its discovery, the phenomenon is already being used therapeutically in human clinical trials, and biotechnology companies that focus on RNA-interference-based therapeutics are already publicly traded.

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Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes.

Clotilde Théry, Livine Duban, Elodie Segura … (2002)

Dendritic cells (DCs) secrete vesicles of endosomal origin, called exosomes, that bear major histocompatibility complex (MHC) and T cell costimulatory molecules. Here, we found that injection of antigen- or peptide-bearing exosomes induced antigen-specific naïve CD4+ T cell activation in vivo. In vitro, exosomes did not induce antigen-dependent T cell stimulation unless mature CD8alpha- DCs were also present in the cultures. These mature DCs could be MHC class II-negative, but had to bear CD80 and CD86. Therefore, in addition to carrying antigen, exosomes promote the exchange of functional peptide-MHC complexes between DCs. Such a mechanism may increase the number of DCs bearing a particular peptide, thus amplifying the initiation of primary adaptive immune responses.

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Exosomes are natural carriers of exogenous siRNA to human cells in vitro

Tatyana Shtam, Roman Kovalev, Elena Varfolomeeva … (2013)

Background Exosomes are nano-sized vesicles of endocytic origin that are involved in cell-to-cell communication including shuttle RNA, mainly mRNA and microRNA. As exosomes naturally carry RNA between cells, these particles might be useful in gene cancer therapy to deliver therapeutic short interfering RNA (siRNA) to the target cells. Despite the promise of RNA interference (RNAi) for use in therapy, several technical obstacles must be overcome. Exogenous siRNA is prone to degradation, has a limited ability to cross cell membranes and may induce an immune response. Naturally occurring RNA carriers, such as exosomes, might provide an untapped source of effective delivery strategies. Results This study demonstrates that exosomes can deliver siRNA to recipient cells in vitro. The different strategies were used to introduce siRNAs into human exosomes of various origins. The delivery of fluorescently labeled siRNA via exosomes to cells was confirmed using confocal microscopy and flow cytometry. Two different siRNAs against RAD51 and RAD52 were used to transfect into the exosomes for therapeutic delivery into target cells. The exosome-delivered siRNAs were effective at causing post-transcriptional gene silencing in recipient cells. Moreover, the exosome-delivered siRNA against RAD51 was functional and caused the massive reproductive cell death of recipient cancer cells. Conclusions The results strongly suggest that exosomes effectively delivered the siRNA into the target cells. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated in vitro by the strong knockdown of RAD51, a prospective therapeutic target for cancer cells. The results give an additional evidence of the ability to use human exosomes as vectors in cancer therapy, including RNAi-based gene therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Arch Med Sci

Journal ID (iso-abbrev): Arch Med Sci

Journal ID (publisher-id): AMS

Title: Archives of Medical Science : AMS

Publisher: Termedia Publishing House

ISSN (Print): 1734-1922

ISSN (Electronic): 1896-9151

Publication date (Electronic): 24 October 2016

Publication date (Print): 01 December 2016

Volume: 12

Issue: 6

Pages: 1324-1326

Affiliations

[1 ]National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran

[2 ]Neurogenic Inflammation Research Center, Department of Medical Biotechnology, Mashhad University of Medical Sciences, Mashhad, Iran

[3 ]Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Lodz, Poland

[4 ]Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Author notes

Corresponding author: Amirhossein Sahebkar PhD, Biotechnology Research Center, Mashhad University of Medical Sciences, Vakilabad blvd., 9177948564 Mashhad, Iran. Phone: +989151221496, Fax: +985138002287. E-mail: sahebkara@ 123456mums.ac.ir

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Publisher ID: 28533

DOI: 10.5114/aoms.2016.62911

PMC ID: 5108394

PubMed ID: 27904525

SO-VID: 53fbb51b-4651-4382-9776-0c09d0acccf9

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.

History

Date received : 13 March 2016

Date accepted : 18 March 2016

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Exosomes as nanocarriers for siRNA delivery: paradigms and challenges

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Most cited references 10

The promises and pitfalls of RNA-interference-based therapeutics.

Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes.

Exosomes are natural carriers of exogenous siRNA to human cells in vitro

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