Chimeric antigen receptor T-cell (CAR-T) therapy has become a powerful treatment for certain cancers, yet its clinical application remains limited by complex manufacturing, high costs, and logistical barriers. In vivo CAR-T therapy is emerging as a transformative alternative, aiming to generate functional CAR-T cells directly inside the patient’s body through advanced gene delivery technologies.
Unlike conventional CAR-T therapy, which requires the collection, genetic modification, and expansion of T cells outside the body, in vivo CAR-T bypasses ex vivo manufacturing entirely. By delivering genetic instructions directly to endogenous T cells, this approach preserves native T-cell function, shortens treatment timelines, and has the potential to improve accessibility and scalability.
The article provides a comprehensive and up-to-date overview of this rapidly evolving field. It systematically analyzes the major delivery platforms used for in vivo CAR-T generation, including viral vectors and non-viral lipid nanoparticle systems. Viral platforms, such as lentiviral and adeno-associated viral vectors, offer durable CAR expression and are currently favored in oncology indications. In contrast, lipid nanoparticle–based mRNA delivery enables transient and controllable CAR expression, which may be particularly advantageous for autoimmune diseases where reversibility and safety are critical.
In addition to platform engineering, the article summarizes recent global clinical progress. Over the past two years, in vivo CAR-T therapies have advanced from preclinical studies to early-stage clinical trials, with encouraging results reported in hematologic malignancies and autoimmune diseases. Notably, early clinical evidence demonstrates that in vivo–generated CAR-T cells can achieve meaningful clinical responses while maintaining manageable safety profiles. The review also highlights the entry of solid tumors into the in vivo CAR-T clinical pipeline, marking an important step toward addressing long-standing unmet needs in cancer therapy.
The article further discusses key translational challenges that must be addressed for broader clinical adoption. These include achieving precise T-cell targeting, minimizing off-target gene expression, controlling CAR-T cell persistence, and managing immune responses against delivery vectors. Emerging strategies such as engineered targeting ligands, inducible safety switches, and improved vector design are outlined as potential solutions.
Regulatory and clinical development considerations are also examined. Because in vivo CAR-T therapy lies at the intersection of gene therapy and cell therapy, clear regulatory frameworks and appropriate evaluation endpoints are still being established. The article emphasizes the importance of integrating biomarker analysis, pharmacokinetic and pharmacodynamic modeling, and long-term safety monitoring into future clinical trials.
Overall, this work positions in vivo CAR-T therapy as a paradigm shift in adoptive cell therapy, reframing CAR-T not as a laboratory-manufactured product but as an in situ gene-programming strategy. By integrating engineering advances, clinical evidence, and translational insights, the article provides a forward-looking roadmap for the rational development of in vivo CAR-T therapies across cancer and autoimmune diseases.
The authors are affiliated with the National Cancer Center and the Chinese Academy of Medical Sciences, institutions committed to advancing translational research and innovative therapies to improve patient outcomes.
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