Endosomal escape: A bottleneck for LNP-mediated therapeutics

Sushmita Chatterjee, Edo Kon, Preeti Sharma, Dan Peer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Lipid nanoparticles (LNPs) have recently emerged as a powerful and versatile clinically approved platform for nucleic acid delivery, specifically for mRNA vaccines. A major bottleneck in the field is the release of mRNALNPs from the endosomal pathways into the cytosol of cells where they can execute their encoded functions. The data regarding the mechanism of these endosomal escape processes are limited and contradicting. Despite extensive research, there is no consensus regarding the compartment of escape, the cause of the inefficient escape and are currently lacking a robust method to detect the escape. Here, we review the currently known mechanisms of endosomal escape and the available methods to study this process. We critically discuss the limitations and challenges of these methods and the possibilities to overcome these challenges. We propose that the development of currently lacking robust, quantitative high-throughput techniques to study endosomal escape is timely and essential. A better understanding of this process will enable better RNA-LNP designs with improved efficiency to unlock new therapeutic modalities.

Original languageEnglish
Article numbere2307800120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number11
DOIs
StatePublished - 12 Mar 2024

Funding

FundersFunder number
Shmunis Family Foundation
Lewis Trust
Yoran Institute for Human Genome Research
European Research Council101055029
European Research Council
Horizon 2020 Framework Programme825828
Horizon 2020 Framework Programme
Israel Science Foundation2012/20
Israel Science Foundation

    Keywords

    • LNPs
    • RNA vaccines and therapeutics
    • endo-lysosomes
    • endosomal escape
    • mRNA

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