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mRNA驱动CAR-T细胞治疗的研究与转化前景

Research and Future Applications of mRNA-Driven CAR-T Cell Therapy

  • 摘要: mRNA驱动的CAR-T兼具非基因组整合、表达时程可控及体内生成潜力,是非病毒CAR-T的重要方向。当前瓶颈已不只是能否表达CAR,而是如何在充分的效应持续时间、可回撤性及体内递送效率之间取得平衡。常规线性mRNA工艺成熟,但表达持续时间较短;环状mRNA可延长表达时程。相比常规环状mRNA,无痕环状mRNA的核心优势在于减少经典环化体系的外源疤痕序列,降低分子结构的不确定性及质量控制的复杂性,更适用于CAR等长编码序列的递送。未来临床转化的核心挑战包括T细胞特异性递送、体内表达时程调控、重复给药的安全性及规模化制备与质量标准的建立。本文综述了mRNA-CAR-T的研究进展,并重点讨论无痕环状mRNA的构建、功能价值及转化前景。

     

    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.

     

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