Therapeutic RNA delivery by Extracellular Vesicle mimetics

Assoc. Prof. Dr. Pieter Vader1) – University Medical Center Utrecht, The Netherlands

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1.

Assist. Professor Dr. Pieter VaderUniversity Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands

People involved

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Abstract

RNA-based therapeutics, including siRNA, mRNA and RNA components of the CRISPR/Cas9 machinery, have unprecedented therapeutic potential and hold the promise of treating any disease with a genetic component. However, inefficient delivery into diseased cells hinders their clinical progress, which remains limited to applications such as treatment of liver diseases (where most nanoparticles accumulate) or vaccination. Consequently, there is an urgent need for novel approaches to overcome the delivery challenges.

Recently, an endogenous RNA transport system has emerged, based on the cellular release and uptake of extracellular vesicles (EVs).1) EVs are naturally equipped to transfer biological cargo, including RNA, in a selective manner, thereby influencing the function(s) of recipient cells.2) As nature’s choice for intercellular transport, EVs utilize endogenous mechanisms for targeting, internalization and trafficking in vitro and in vivo in order to effectively deliver their RNA cargo. EV surface proteins are of critical importance for this transport function, which raises the possibility to improve synthetic carriers through EV-based engineering by incorporating EV surface proteins, creating EV mimetics.

The aim of this project is to prepare and functionally evaluate the use of EV mimetics for therapeutic RNA delivery. This work may result in a prototype new generation delivery system based on EV mimetics and will significantly advance our comprehensive understanding of the natural targeting and RNA delivery mechanisms of such systems.

Benefit for the community

When successful, this work will lead to increased interest from academia and industry for the phospholipid research area. Both the RNA therapeutics market and the extracellular vesicle therapeutic market have enormous momentum and are one of the fastest growing therapeutic classes in the pharmaceutical market. Successful novel treatments based on RNA will drastically lower burden to patients and care takers.

Challenges for therapeutic delivery of RNA mainly lie in the area of safety and in therapeutic delivery beyond the liver. EV mimetics offer great potential to overcome specifically these grand challenges.

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References:
1.
Rodríguez DA, Vader P, 2022
Extracellular Vesicle-Based Hybrid Systems for Advanced Drug Delivery
Pharmaceutics 14, 267
2.
Elsharkasy OM, Nordin JZ, Hagey DW, de Jong OG, Schiffelers RM, Andaloussi SE, Vader P, 2020
Extracellular vesicles as drug delivery systems: Why and how?
Adv. Drug Deliv. Rev. 159, 332-343
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