In vivo CAR-T therapy: The shift from ex vivo culturing to direct in situ immune reprogramming.

Transient T cell therapies.

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

In vivo engineering of CAR immune cells by nonviral nanoparticles.

Nonviral NPs are poised to redefine CAR therapy by enabling scalable, off-the-shelf immune interventions for cancer, autoimmune, and fibrotic diseases.

The landscape of genetic medicines for in vivo T cell reprogramming.

Key challenges related to the biodistribution, activation, and persistence of modified T cells are highlighted, with an emphasis on the potential of these strategies for treating not only blood cancers but also solid tumors, autoimmune diseases, and beyond.

In vivo CAR‑T therapy: recent progress and future directions

In-vivo CAR-T Cell Engineering: A Narrative Review of Emerging Delivery Strategies and Their Potential Future Impact on Accessibility

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a groundbreaking advancement in cancer immunotherapy, progressively improving over decades and producing remarkable clinical outcomes. This review examines the evolution of CAR-T cell therapy by comparing ex vivo and newer in-vivo approaches, evaluating the four primary delivery vehicles used for in-vivo CAR-T therapy, and discussing their implications for safety, scalability, accessibility and future development. Although ex vivo CAR-T therapy has demonstrated substantial clinical success, its complex manufacturing process, high cost, prolonged production time, and reliance on specialized facilities limit patient access worldwide. In contrast, in-vivo CAR-T therapy genetically reprograms T cells directly within the body, eliminating external manipulation of T cells and thus many of the logistical barriers associated with ex vivo manufacturing. Four primary delivery vehicles have shown immense progress within-vivo CAR-T cell therapy: lentiviral vectors, lipid nanoparticles, polymeric nanoparticles, and virus-like particles. Each delivery platform offers distinct advantages and limitations in terms of efficacy, safety, and scalability. Most evidence for in-vivo CAR-T therapy to date comes from preclinical and early-phase studies; if these approaches continue to mature, they may offer a more scalable, cost-effective, and accessible alternative to traditional ex vivo CAR-T therapy, though this remains a projected rather than demonstrated benefit.