Engineering protein toxins to modulate the intracellular trafficking of biologics into exosomes for third order drug targeting

MINIREVIEW

EJEV (2022), Vol 2, 1-6

Published online: 16 February 2022

Full Text (Feron ~1426kb)

Benedita KL Feron and Simon CW Richardson*

Exogenix Laboratory, School of Science, Faculty of Engineering and Science, University of Greenwich, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK

*Correspondence to: Simon Richardson, S.C.W.Richardson@Greenwich.ac.uk

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© Copyright The Author(s). This is an open access article, published under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0). This license permits non-commercial use, distribution and reproduction of this article, provided the original work is appropriately acknowledged, with correct citation details.

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ABSTRACT

The successful use of mRNA as a vaccine to limit the effects of COVID-19 has highlighted the potential of RNA based drugs. However, the use of small interfering (si)RNA (or antisense oligonucleotides (ASOs)) as therapeutics remains limited by the availability of safe and robust drug delivery technology that can deliver intact RNA to the cytosol of tissues beyond the liver or muscle. New knowledge regarding the regulation of intracellular compartmentalisation associated with membrane trafficking has led to the identification of new problems and opportunities within the field of drug delivery. One of the technologies that has emerged is the use of attenuated toxins for the cytosolic delivery of macromolecules. Unlike charged lipids or synthetic polymers, these molecules do not display charge limited PKPD or toxicity profiles intimately linked to their ability to mediate transfection. Anthrax toxin uses intraluminal vesicles (ILVs) as an intermediary compartment en route to the cytosol of mammalian cells. These ILVs can be subsequently secreted as exosomes and herein is an opportunity to load selected nucleic acid or protein drugs into exosomes. Exosomes loaded in this manner have the potential to transport bioactive payloads across intercellular space to their target, whilst protecting their luminal cargo from hydrolytic enzymes or from the host’s immune response before effecting cytosolic delivery. Following such a rationale, engineering biology may provide a valuable platform for third order drug targeting and facilitate the intracellular delivery of RNA drugs to cells and tissues beyond striated muscle and the liver.

Keywords: Antisense, siRNA, Toxin, Cytosol, Endocytosis, Exosomes, Biologics

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