The Body as a Drug Factory: The Emergence of In Vivo-Generated CAR Therapies
1. Repairing Immune Cells Directly Inside the Human Body
CAR‑T therapy, which has long been a hope for cancer treatment, required extracting a patient’s blood, genetically modifying the cells ex vivo, and reinfusing them. This approach is costly and time‑consuming. Recently, scientists have accelerated the development of “in vivo CAR” technology that edits immune cells directly within the patient’s body, turning them into cancer‑killing agents.
2. Viruses and Nanoparticles: Precise Couriers that Penetrate Tumors
To edit cells in situ, viral vectors such as lentivirus and adeno‑associated virus (AAV) as well as non‑viral delivery methods like lipid nanoparticles (LNP) are evolving simultaneously. These platforms enable the on‑demand generation of CAR‑T for hematologic malignancies, CAR‑NK for solid tumors, and CAR‑M (macrophage) that remodels the immune microenvironment within tumor tissue, thereby breaching the tumor’s defensive barriers.
3. AI and Smart Systems Creating “Synthetic Immunity”
Beyond simple gene insertion, artificial intelligence (AI) now designs patient‑specific therapeutics and employs smart delivery vehicles such as circular RNA. A “synthetic immune system” that coordinates multiple immune cell types to attack cancer is becoming a reality, offering a new weapon capable of controlling the complex tumor ecosystem that single‑cell approaches cannot overcome.
4. Future Significance and Outlook
If commercialized, this technology could allow hospitals to produce personalized immune therapies on demand without complex manufacturing facilities. Ultimately, it may enable far cheaper and faster treatment of cancer and many other refractory diseases, providing a genuine turning point that offers a realistic chance of cure for cancer patients worldwide.
In vivo chimeric antigen receptor (CAR) cell therapy is undergoing a transformative shift from conventional ex vivo manufacturing toward in situ cellular editing, aiming to generate functional CAR-engineered immune cells directly within patients through targeted vector delivery, thereby significantly enhancing therapeutic accessibility and applicability. While rapid advances have been made in both viral (lentiviral and adeno-associated viral vectors) and non-viral (lipid nanoparticle) delivery platforms, along with the expansion of effector cell lineages including CAR-T, CAR-NK, and CAR-M, critical translational bottlenecks remain. These include insufficient delivery precision, limited cellular persistence, immunosuppressive tumor microenvironment (TME) resistance, and challenges in safety controllability. This review systematically examines the working mechanisms and limitations of current delivery platforms for in vivo gene transfer. It provides a comprehensive comparison of how CAR-T, CAR-NK, and CAR-M platforms employ distinct yet complementary strategies to address tumor heterogeneity, solid tumor physical and immune barriers, and the specificity constraints of in situ editing. Furthermore, we highlight emerging frontiers such as artificial intelligence-guided personalized therapy design, smart delivery systems (logic-gated CARs, circular RNA vectors), and the development of multicellular synergistic "synthetic immune systems." By integrating multidisciplinary perspectives, this review not only offers a comprehensive roadmap bridging fundamental mechanisms to clinical translation but also lays a theoretical and technical foundation for advancing the next generation of safe, precise, and efficacious in vivo CAR therapies.
It eliminates the cumbersome and expensive step of expanding cells outside the patient’s body, enabling the therapeutic agent to be produced directly inside the patient. This dramatically reduces treatment costs and accelerates therapy delivery, bringing us closer to a world where anyone can safely and promptly overcome cancer—a truly valuable advancement.