Non-viral and mRNA-based strategies for next-generation CAR-T cell therapy.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematologic malignancies, but its broader application remains limited by the complexity, cost, manufacturing time, and integration-related risks associated with viral vector-based engineering. These constraints have become increasingly important as CAR-T strategies are being extended to solid tumors, autoimmune diseases, and in vivo CAR-T generation, while mRNA therapeutics and non-viral delivery technologies continue to advance. However, non-viral platforms and mRNA engineering are often discussed separately, and a unified translational perspective is still lacking. In this review, we examine how mRNA engineering can be integrated with non-viral delivery systems, including lipid nanoparticles, electroporation, and exosome-based platforms, to support safer and more flexible ex vivo and in vivo CAR-T generation. We further discuss key barriers to clinical translation, including limited expression durability, cell-selective delivery, manufacturing scalability, and regulatory considerations, and highlight the emerging contribution of computational approaches to sequence and carrier optimization. Together, these advances support a timely reassessment of non-viral mRNA-based CAR-T engineering as a practical framework for the development of next-generation cell therapies.