Pharmacometric modeling of lipid nanoparticle-encapsulated mRNA therapeutics and vaccines: A systematic review

Significant progress has been made in the development of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA)-based modalities with numerous candidates entering clinical trials. These novel modalities require the application of innovative quantitative models to inform the development of mRNA-LNP-based candidates. To this end, we conducted a comprehensive search of registered clinical trials related to mRNA-based modalities on ClinicalTrials.gov, summarizing the current advancements of mRNA-LNP-based modalities and their expanding therapeutic applications. Also, we performed a thorough review of quantitative models related to mRNA-LNP-based modalities from PubMed, Google Scholar, and Embase databases, exploring the model structures employed to capture the in vivo processes of mRNA-LNP, along with their current applications. Between 2002 and October 28, 2024, around 189 clinical trials were registered on ClinicalTrials.gov, encompassing approximately 132 unique mRNA-based modalities targeting 18 disease areas. There are 15 studies that have published quantitative models supporting both the preclinical and clinical development of mRNA-LNP-based therapeutics. Detail regarding quantitative modeling of mRNA-LNP, especially absorption, distribution, metabolism, and excretion, as well as the activation processes of immune responses induced by mRNA-LNP-based vaccines are reviewed. Furthermore, we offer insights for future research related to mRNA-LNP-related models, aimed at enhancing predictive performance and facilitating the expedited advancement of mRNA-LNP-related clinical development.