In vivo transduction of CAR T cells: Pharmacological principles, delivery platforms, and the road to clinical translation.

Chimeric antigen receptor (CAR) T cell therapy has fundamentally altered the treatment landscape for hematological malignancies, yet the autologous ex vivo manufacturing process that underpins commercially available products imposes severe constraints on access, scalability, and cost. In vivo CAR T cell generation can be achieved by direct systemic administration of gene delivery vehicles engineered to selectively transduce endogenous T lymphocytes. This approach reconceives the patient's own lymphoid organs as a bioreactor. Two major platforms are now entering clinical testing: engineered viral vectors that stably integrate a CAR transgene, and lipid nanoparticles (LNPs) that deliver CAR-encoding RNA for transient expression. This review examines the biological rationale, delivery engineering, immunological barriers, CAR payload design, early clinical evidence, and future directions of this field. Particular emphasis is placed on the pharmacological principles that distinguish in vivo from ex vivo approaches, and on the transformative potential for indications that lie beyond the current reach of conventional CAR T cell therapy.