In Vivo Engineered CAR-T Cell Therapy: Lessons Built from COVID-19 mRNA Vaccines

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized cancer immunotherapy but continues to face significant challenges that limit its broader application, such as antigen targeting, the tumor microenvironment, and cell persistence, especially in solid tumors. Meanwhile, the global implementation of mRNA vaccines during the COVID-19 pandemic has highlighted the transformative potential of mRNA and lipid nanoparticle (LNP) technologies. These innovations, characterized by their swift development timelines, precise antigen design, and efficient delivery mechanisms, provide a promising framework to address some limitations of CAR-T therapy. Recent advancements, including mRNA-based CAR engineering and optimized LNP delivery, have demonstrated the capacity to enhance CAR-T efficacy, particularly in the context of solid tumors. This review explores how mRNA-LNP technology can drive the development of in vivo engineered CAR-T therapies to address current limitations and discusses future directions, including advancements in mRNA design, LNP optimization, and strategies for improving in vivo CAR-T functionality and safety. By bridging these technological insights, CAR-T therapy may evolve into a versatile and accessible treatment paradigm across diverse oncological landscapes.

Keywords: CAR-T therapy; immune response regulation; lipid nanoparticles; mRNA technology; mRNA vaccines.

Figure 1

mRNA-LNP Platforms: The Foundation of COVID-19 mRNA Vaccines. (A) Engineering of mRNA, exemplified by COVID-19 vaccines encoding the pre-fusion-stabilized spike glycoprotein, demonstrates key strategies, including codon optimization, avoidance of secondary structures, and nucleotide modifications (e.g., pseudouridine, N1-methylpseudouridine), that enhance mRNA stability, translational efficiency, and minimize immunogenicity. (B) Lipid nanoparticles (LNPs), composed of ionizable lipids, phospholipids, cholesterol, and PEG-modified lipids, provide protection, immune modulation, and tunable delivery properties for effective mRNA transport. LNPs facilitate efficient cytoplasmic delivery of mRNA via pH-sensitive endosomal escape, a critical mechanism applicable both to vaccines and emerging in vivo CAR-T cell therapies.

Figure 2

Schematic Representation of mRNA-Based CAR-T Cell Engineering and Key Advantages. The schematic illustrates mRNA-based engineering of CAR-T cells using LNP technology. In this process, CAR-encoding mRNA, incorporating optimized nucleotide modifications, is encapsulated into LNPs for targeted in vivo delivery. Upon cellular uptake, mRNA undergoes efficient cytoplasmic translation into CAR proteins, transiently expressed on T cell surfaces, to mediate precise tumor targeting. Key advantages of this mRNA-LNP platform include flexible and personalized mRNA design, precise control over dosing and timing (enabling pulsed administration strategies), and modulation of immune responses to optimize therapeutic efficacy while minimizing potential adverse effects. These features collectively position mRNA-LNP-induced CAR-T therapy as a promising approach for adaptable, safe, and efficient cancer immunotherapy.