Abstract:
mRNA-driven CAR-T cell therapy has emerged as an important direction in non-viral CAR-T development because it avoids genomic integration, enables the temporal regulation of CAR expression, and facilitates the
in vivo generation of CAR-T cells. The key challenge is no longer simply whether CAR expression can be achieved, but how to balance a sufficient duration of effector activity with reversibility and efficient in vivo delivery. Conventional linear mRNA benefits from well-established manufacturing processes but is limited by its relatively short expression period, whereas circular mRNA can extend the expression window. Compared with conventional circular mRNA, scarless circular mRNA minimizes exogenous scar sequences introduced by classical circularization systems, thereby reducing uncertainty in molecular structure and simplifying quality control. These features may make it particularly suitable for delivering long coding sequences such as CAR constructs. Major challenges for future clinical translation include T cell-specific delivery, precise control of the
in vivo expression duration, the safety of repeated administration, and the development of scalable manufacturing processes and quality standards. This review summarizes recent advances in mRNA-engineered CAR-T cell therapy, focusing on the construction, functional value, and translational potential of scarless circular mRNA.