In vivo CAR T cell engineering: design principles and open questions.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, leading to seven FDA-approved products, but widespread adoption has been limited by costly and complex manufacturing and administration. Several methods have emerged to directly reprogram T cells within patients, with the potential to simultaneously improve potency, reduce costs, and broaden accessibility. While early clinical studies demonstrate safety and therapeutic activity, critical questions remain regarding long-term efficacy, the interplay between means of delivery and host biology, and optimal disease indications for each delivery approach. This review summarizes the preclinical and clinical data for state-of-the-art viral and nonviral approaches for in vivo CAR-T engineering, discusses their opportunities and limitations, and highlights key open questions that will shape the maturation of this emerging field.