The strategies and advances of mRNA translation booster

Abstract

The therapeutic efficacy and safety of mRNA-based drugs in immunological and nonimmunological applications are critically dependent on the translated protein yield, which requires precise modulation of mRNA expression kinetics. Among the factors influencing mRNA translation, immunogenicity and stability are pivotal in determining the longevity of protein production. Current optimization strategies have integrated (1) molecular engineering (e.g., modified nucleotides), (2) advanced delivery systems (e.g., lipid nanoparticles), and (3) adjuvant drug synergy. This review focuses on co-delivered adjuvant drugs and introduces the concept of "mRNA translation boosters" for the first time. mRNA translation boosters are classified as small-molecule compounds and macromolecular agents that improve translational fidelity through mechanisms including blockade of pattern recognition receptors, modulation of inflammatory cascades, facilitation of endosomal escape, and protection against enzymatic degradation. As clinically validated with COVID-19 mRNA vaccines, these boosters have now demonstrated expanded utility in gene editing therapies and protein replacement applications. This review addresses the immunological challenges encountered during mRNA transfection and translation while summarizing existing mRNA translation boosters that optimize protein expression kinetics. By establishing a mechanistic framework for booster selection and employment, this work provides translational guidance for advancing nucleic acid therapeutics towards their maximum clinical potential.

Keywords

mRNA expression / Immunogenicity / Translation boosters / Nucleic acid therapeutics

Conflicts of interest

The authors declare that there is no conflicts of interest.

Acknowledgments

This work was supported by the National Key R&D Program of China (2023YFC340200), National Natural Science Foundation of China (No. 82404520, No. 82273862, No. 824B2106), the China Postdoctoral Science Foundation (2024M752834), the China National Postdoctoral Program for Innovative Talents (BX20230321), and Leading Goose + "X" R&D research and development programme (2024C03088).

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