In Vivo CAR-T Therapies-A New Era of Programmable Immunity.

Ex vivo chimeric antigen receptor (CAR) T cell therapies have achieved remarkable clinical success over the past decade, enabling effective treatment of several hematologic malignancies once considered incurable. However, their broader use remains limited. Barriers include complex and costly manufacturing, long production timelines, and risk of significant side effects and toxicities, challenges that have been further exacerbated by the reduced investment across the biotech sector since 2022. Emerging in vivo CAR-T approaches seek to overcome many of these limitations by generating CAR-T cells directly within the patient, most commonly using lentiviral or lipid nanoparticles (LNPs) delivery vectors. This strategy has the potential to streamline production, allow more tunable and repeatable dosing, and markedly reduce overall costs. However, it also raises new questions regarding genomic safety, the specificity and durability of CAR expression, host immune responses, pharmacokinetics, and regulatory oversight. In this review, we summarize the major and emerging in vivo CAR-T delivery platforms-analyzing their underlying technology, preclinical and clinical performance, and developmental paths-and discuss the scientific, technical, and biological challenges shaping this rapidly emerging field. We further outline future directions and opportunities in the field of programmable T cell immunity.