Catch me if you can: How mRNA therapeutics are delivered into cells


Date:
December 9, 2021
Source:
Max Planck Institute of Molecular Cell Biology and Genetics
(MPI-CBG)
Summary:
In recent years, ribonucleic acid (RNA) has emerged as a powerful
tool for the development of novel therapies. RNA is used to copy
genetic information contained in our hereditary material, the
deoxyribonucleic acid (DNA), and then serves as a template for
building proteins, the building blocks of life. Delivery of RNA
into cells remains a major challenge for the development of novel
therapies across a broad range of diseases.



FULL STORY ==========================================================================
DNA (deoxyribonucleic acid) contains the genetic information required for
the development and maintenance of life. This information is communicated
by messenger ribonucleic acid (mRNA) to make proteins. mRNA-based
therapeutics have the potential to address unmet needs for a wide variety
of diseases, including cancer and cardiovascular disease. mRNA can be
delivered to cells to trigger the production, degradation or modification
of a target protein, something impossible with other approaches. A key challenge with this modality is being able to deliver the mRNA inside
the cell so that it can be translated to make a protein. mRNA can be
packed into lipid nanoparticles (LNPs) NOT- small bubbles of fat NOT-
that protect the mRNA and shuttle it into cells.

However, this process is not simple, because the mRNA has to pass the
membrane before it can reach its site of action in the cell interior,
the cytoplasm.


========================================================================== Researchers in the team of MPI-CBG director Marino Zerial are experts in visualizing the cellular entry routes of molecules in the cell, such as
mRNA with high-resolution microscopes. They teamed up with scientists
from AstraZeneca who provided the researchers with lipid nanoparticle prototypes that they had developed for therapeutic approaches to follow
the mRNA inside the cell. The study is published in the Journal of
Cell Biology.

"To be delivered, the mRNA must make a long journey. Enclosed in
the fatty LNP bubble, it needs to get into the cell first," explains
Marino Zerial. "The LNPs arrive at the cell surface where they bind to receptors. They are then taken up into specialized membrane-enclosed compartments called endosomes. At this point, the mRNA is inside the
cells but surrounded by two barriers, the fatty bubble and the endosome
wall or more correctly, membrane. The challenge for the mRNA is to escape
both barriers to reach the cytoplasm where it serves as a template to
make proteins. We know that only a tiny fraction of RNA molecules are
able to escape into the cytoplasm." Internalized cargo molecules, like
the LNPs, are first transported to "early" endosomes. These are logistic centres that distribute cargo molecules to various destinations in the
cell. They either recycle molecules to the cell surface or degrade them
in late endosomes and lysosomes. So far, people thought that the mRNA
escapes from late endosomes exploiting their very acidic content. "With
single molecule microscopy techniques," explains Prasath Paramasivam,
the first author of the study, "we could visualize for the first time
the mRNA in the LNP inside the endosomes of cells. We also captured the
actual escape of the mRNA, which happened in the tubules of the recycling endosomes, which are only mildly acidic." "Our results imply that sending
the LNP-mRNA to late endosomes is counterproductive for delivery and only increases cell toxicity." says Zerial. These findings help understanding
the mechanism of mRNA escape from endosomes in more detail.

Marino Zerial summarizes: "The LNP delivery system for mRNA necessitates
high doses due to the low endosomal escape efficiency. Knowing
where the mRNA goes and how it can escape the endosomes allows
us to develop better vehicles for more efficient delivery, at
lower dosage. We can improve the mRNA delivery system so it can
be used for therapeutic applications, for example cancer treatment." ========================================================================== Story Source: Materials provided by Max_Planck_Institute_of_Molecular_Cell_Biology_and
Genetics_(MPI-CBG). Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Prasath Paramasivam, Christian Franke, Martin Sto"ter, Andreas
Ho"ijer,
Stefano Bartesaghi, Alan Sabirsh, Lennart Lindfors, Marianna
Yanez Arteta, Anders Dahle'n, Annette Bak, Shalini Andersson,
Yannis Kalaidzidis, Marc Bickle, Marino Zerial. Endosomal escape
of delivered mRNA from endosomal recycling tubules visualized at
the nanoscale.

Journal of Cell Biology, 2022; 221 (2) DOI: 10.1083/jcb.202110137 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211209124315.htm

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