Deciphering the biological fate of mRNA-LNP-based biologics: A perspective from tissue to intracellular distribution

The remarkable clinical success of mRNA-lipid nanoparticle (mRNA-LNP) vaccines, particularly evidenced by their pandemic-era impact and subsequent 2023 Nobel Prize recognition, has intensified global efforts to expand their application toward therapeutic biologics. Despite showing strong preventive effects, there are still fundamental knowledge gaps in comprehensively defining the hierarchical biological trajectory of mRNA-LNP formulations, which spans from initial systemic exposure, tissue-specific biodistribution, and intracellular delivery to ultimate protein expression dynamics. These unresolved mechanistic questions pose significant constraints on the rational design of next-generation mRNA-LNP therapeutics, which face increased demands for precision dosing, therapeutic efficacy optimization, and enhanced safety profiles. This review discusses the in vivo fate of mRNA-LNP, focusing specifically on blood/tissue/cellular distribution and kinetics/exposure profiles of both intact mRNA-LNP and dissociated components post-administration. It discusses key factors influencing the distribution of expressed protein and summarizes the corresponding research toolkits along with their advantages and disadvantages. Additionally, it compiles strategies to enhance delivery efficacy, tissue tropism, and safety profiles of mRNA-LNP. We anticipate a better understanding of the biological processes and dynamic pattern of mRNA-LNP, which will accelerate the development of next-generation mRNA biologics with predictable safety and delivery efficiency. Systematically characterizing the biological fate of mRNA-LNPs, from initial systemic exposure to tissue-specific biodistribution and intracellular delivery, and ultimately to protein expression dynamics, may benefit the rational development of next-generation mRNA-LNP therapeutics.