Engineering mRNA therapeutics for protein supplementation: Challenges and future horizons

Abstract

Messenger RNA (mRNA) protein replacement therapy harnesses synthetic mRNA to direct endogenous protein synthesis, offering a versatile approach to restore or substitute proteins that are absent or dysfunctional in disease. Here, we review recent advances that have transformed this concept into a promising therapeutic platform, summarizing progress in mRNA design, delivery technologies, and preclinical and clinical applications across metabolic, oncological, and cardiovascular disorders. We also examine persistent challenges, including achieving precise tissue targeting, extending expression duration, and balancing immune tolerance with translation efficiency, that define the next frontier for clinical translation. By systematically analyzing these obstacles and evaluating emerging solutions, such as next-generation mRNA architectures, targeted biomaterial platforms, and programmable expression control, the review proposes new conceptual and technological directions for the next phase of mRNA therapeutic development. Collectively, these insights provide a structure for advancing mRNA protein replacement from proof-of-concept studies toward a broadly applicable platform for precision medicine.

Keywords

mRNA therapy / protein replacement / gene therapy / lipid nanoparticles / in vivo expression / mRNA vaccines

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