In vivo CAR therapies: Turning the patient into their own CAR factory.

Over the past decade, ex vivo autologous chimeric antigen receptor (CAR)-T-cell therapies have reshaped the treatment of B-cell malignancies. Despite their remarkable clinical efficacy, their application remains limited by complex manufacturing processes, demanding logistics, long turnaround times, and substantial costs. In vivo CAR approaches are emerging as a potential solution to address these barriers by enabling direct induction of CAR expression in T cells and other immune cells through in-patient delivery of genetic constructs. This review provides an overview of the current landscape of in vivo CAR therapies. We describe the major delivery platforms under clinical development, with a focus on lentiviral vectors (LVVs) and lipid nanoparticles (LNPs), and discuss their distinct features in terms of manufacturing, mechanism of action, safety, therapeutic applications, and optimization strategies. We also summarize ongoing clinical trials exploring in vivo CAR approaches for hematologic malignancies, solid tumors, and autoimmune diseases. Finally, we highlight the key scientific and clinical challenges that remain, and examine strategies under investigation to overcome these limitations and advance in vivo CAR therapies toward broader clinical translation.