Critical considerations of mRNA–LNP technology for CAR-T therapy: components, payloads and emerging horizons

Abstract

Chimeric antigen receptor T (CAR-T) therapy has shown great success in treating hematologic tumors. However, the current methods of producing CAR-T cells in vitro and in vivo have drawbacks in terms of high cost, safety issues and efficacy problems. Therefore, there is a need for a more practical and feasible technology platform for CAR-T cell production. Messenger RNA (mRNA) encapsulated in lipid nanoparticles (LNPs) has emerged as a promising technology for CAR-T cell production, given its successful application in vaccine production and potential for industrial scalability. This review focuses on in vivo CAR-T cell production utilizing mRNA–LNP technology. Overcoming biological barriers is a major challenge in targeting T cells with LNPs, highlighting the importance of advancements in LNP delivery. Transient CAR mRNA expression presents significant challenges, emphasizing the necessity to modify and optimize mRNA sequences for enhanced stability, prolonged half-life and improved expression levels. This review provides a comprehensive summary of advances in LNPs and mRNA research, as well as the development of novel nucleic acid generations, including self-amplifying RNA (saRNA) and circular RNA (circRNA), aimed at aiding in the enhancement of mRNA–LNP technology in CAR-T cell therapy.