4.7 Article

A Biopharmaceutical Perspective on Higher-Order Structure and Thermal Stability of mRNA Vaccines

Journal

MOLECULAR PHARMACEUTICS
Volume -, Issue -, Pages -

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.2c00092

Keywords

lipid nanoparticle (LNP); COVID-19; mRNA formulation; RNA delivery; circular dichroism (CD); differential scanning calorimetry (DSC)

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Preservation of the integrity of macromolecular higher-order structure is crucial for the stability of biologic drugs and vaccine products. mRNA-LNPs, similar to biologic drugs, are held together by weak forces, but mRNA vaccines face unique formulation and stabilization challenges due to the instability of unmodified mRNA and its limited history as a drug or vaccine. Encapsulation in LNPs increases the thermal unfolding temperatures of mRNA.
Preservation of the integrity of macromolecular higher-order structure is a tenet central to achieving biologic drug and vaccine product stability toward manufacturing, distribution, storage, handling, and administration. Given that mRNA lipid nanoparticles (mRNA-LNPs) are held together by an intricate ensemble of weak forces, there are some intriguing parallels to biologic drugs, at least at first glance. However, mRNA vaccines are not without unique formulation and stabilization challenges derived from the instability of unmodified mRNA and its limited history as a drug or vaccine. Since certain learning gained from biologic drug development may be applicable for the improvement of mRNA vaccines, we present a perspective on parallels and contrasts between the emerging role of higher-order structure pertaining to mRNA-LNPs compared to pharmaceutical proteins. In a recent publication, the location of mRNA encapsulated within lipid nanoparticles was identified, revealing new insights into the LNP structure, nanoheterogeneity, and microenvironment of the encapsulated mRNA molecules [Brader et al. Biophys. J. 2021, 120, 2766]. We extend those findings by considering the effect of encapsulation on mRNA thermal unfolding with the observation that encapsulation in LNPs increases mRNA unfolding temperatures.

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