Abstract
Messenger RNA (mRNA) is being extensively used in gene therapy and vaccination due to its safety over DNA, in the following ways: its lack of integration risk, cytoplasmic expression, and transient expression compatible with fine regulations. However, clinical applications of mRNA are limited by its fast degradation by nucleases, and the activation of detrimental immune responses. Advances in mRNA applications, with the recent approval of COVID-19 vaccines, were fueled by optimization of the mRNA sequence and the development of mRNA delivery systems. Although delivery systems and mRNA sequence optimization have been abundantly reviewed, understanding of the intracellular processing of mRNA is mandatory to improve its applications. We will focus on lipid nanoparticles (LNPs) as they are the most advanced nanocarriers for the delivery of mRNA. Here, we will review how mRNA therapeutic potency can be affected by its interactions with cellular proteins and intracellular distribution.
Highlights
Pharmaceutics 2021, 13, 945. https://The in vivo administration of Messenger RNA (mRNA) for in situ protein production was first reported in 1990, after intramuscular injection of an mRNA coding a reporter gene [1]
MRNA needs to escape the endosomes, which is a limiting step for productive mRNA delivery, as only ≈ 1–2.5% of mRNA was detected in the cytosol after transfection of human epithelial cells with mRNA lipid nanoparticles (LNPs) made of the ionizable lipid D-LinMC3-DMA [70,71]
Increasing lung accumulation in combination with a 50-fold increase in mRNA expression compared to standard LNPs
Summary
The in vivo administration of mRNA for in situ protein production was first reported in 1990, after intramuscular injection of an mRNA coding a reporter gene [1]. Since RNA molecules are unstable, prone to extracellular nucleases degradation, and are membrane-impermeable, mRNA delivery systems are required to protect them from degradation and to promote their cellular uptake into the targeted cells. NP need to incorporate features to control cell targeting, intracellular trafficking and the intracellular release of the mRNA in the cytoplasm for its translation [20] Another important limitation to the delivery of synthetic mRNA is its recognition as foreign mRNA by intracellular sensors, such as Toll-like receptors (TLRs) 7 and 8. LNPs combine the following several advantages: a high mRNA encapsulation efficiency, can be injected by various routes, preclinical and clinical proof of activity, and stability under storage (reviewed in [3,11,24]). To the cytosol and avoidsthose the lysosome, without triggering deleterious sensors, soparticle, that mRNA can leadtotothe ancytosol efficient protein in the cell. triggering cellularcell uptake of the which leads and avoidsproduction the lysosome, without deleterious cell sensors, so that mRNA can lead to an efficient protein production in the cell
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