mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability

A drawback of the current mRNA-lipid nanoparticle (LNP) COVID-19 vaccines is that they have to be stored at (ultra)low temperatures. Understanding the root cause of the instability of these vaccines may help to rationally improve mRNA-LNP product stability and thereby ease the temperature conditions for storage.


The current COVID-19 mRNA-LNPs vaccines must be stored at (ultra)low temperatures.

The core of LNPs contains mRNA, an ionizable cationic lipid, a neutral lipid and water.

mRNA hydrolysis is the determining factor for mRNA-LNP instability.

Improving stability through mRNA molecule optimization should be prioritized.

Other stabilization options: LNP optimization and dried formulation development.

In this review we discuss proposed structures of mRNA-LNPs, factors that impact mRNA-LNP stability and strategies to optimize mRNA-LNP product stability. Analysis of mRNA-LNP structures reveals that mRNA, the ionizable cationic lipid and water are present in the LNP core. The neutral helper lipids are mainly positioned in the outer, encapsulating, wall. mRNA hydrolysis is the determining factor for mRNA-LNP instability. It is currently unclear how water in the LNP core interacts with the mRNA and to what extent the degradation prone sites of mRNA are protected through a coat of ionizable cationic lipids.

To improve the stability of mRNA-LNP vaccines, optimization of the mRNA nucleotide composition should be prioritized. Secondly, a better understanding of the milieu the mRNA is exposed to in the core of LNPs may help to rationalize adjustments to the LNP structure to preserve mRNA integrity. Moreover, drying techniques, such as lyophilization, are promising options still to be explored.

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Article information: Linde Schoenmaker, Dominik Witzigmann, Jayesh A. Kulkarni, Rein Verbeke, Gideon Kersten, Wim Jiskoot, Daan J.A. Crommelin. International Journal of Pharmaceutics, Volume 601, 2021.

Dominik Witzigmann, one of the authors of this paper was speaking on the topic of mRNA lipid nanoparticle technology at our conference, ExciPerience. To watch the recorded speeches click here:

Lipid Nanoparticles Teaser

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