Review Article: mRNA CARs: An Emerging New-Old Idea

Chimeric antigen receptor (CAR) T cell therapy has transformed cancer immunotherapy. Still, conventional viral vectors carry risks of insertional mutagenesis, are costly to manufacture, and can cause persistent on-target/off-tumor toxicity. Messenger RNA (mRNA) platforms offer a nonintegrating, transient alternative that enables rapid, modular expression of CARs and accessory molecules and can be extensively optimized. mRNA CAR T cells can be manufactured in days, and their transient expression allows repeat dosing and mitigates prolonged toxicity. Preclinical studies show that electroporation or lipid nanoparticle delivery can generate potent CAR-engineered immune cells. Beyond oncology, transient mRNA CARs are explored for autoimmune diseases such as systemic lupus erythematosus, lupus nephritis and myasthenia gravis, where short-lived CAR expression can reset autoreactive B-cell compartments while avoiding long-term immunosuppression. Emerging delivery strategies, including targeted lipid nanoparticles that program T cells in vivo, could eliminate the need for ex vivo cell manufacture and extend CAR therapy to fibrosis and regenerative medicine. Collectively, these developments position mRNA-engineered CARs as a flexible, safer and scalable platform that complements or potentially surpasses viral CAR technologies in oncology, autoimmunity and beyond.