Chimeric antigen receptor T-cell (CAR-T) immunotherapy has emerged as a revolutionary technology in cancer treatment, demonstrating exceptional efficacy particularly in hematologic malignancies. However, traditional ex vivo CAR-T therapies still face significant limitations, including complex preparation processes, high production costs, lengthy preparation cycles, and the requirement for patients to undergo lymphodepletion pretreatment, which restrict their widespread clinical accessibility. As a highly promising innovative strategy, in vivo CAR-T cell therapy delivers gene drugs directly within the body to reprogram the patient′s own T cells in situ, offering the potential to fundamentally resolve these challenges. This paper comprehensively reviews the latest research advances in in vivo CAR-T therapy, focusing on key technological breakthroughs in the two core delivery platforms: viral and non-viral. Regarding viral vectors, lentivirus (LV) and adeno-associated virus (AAV) are achieving specific targeting of T cells through surface modification techniques to enhance transduction efficiency and reduce off-target risks. In the non-viral vector domain, lipid nanoparticles (LNPs) combined with mRNA technology have garnered significant attention for enabling transient CAR expression, reducing cytokine release syndrome (CRS) risks, and avoiding genomic insertion mutations. Recent clinical trials have demonstrated their potential for treating solid tumors. Additionally, the article highlights the advantages of emerging carriers like polymeric nanoparticles and engineered exosomes in terms of low immunogenicity and controllable delivery. Although in vivo CAR-T therapies have progressed from proof-of-concept to multiple human clinical trials, including platforms like INT2104 and VivoVec, widespread adoption remains hindered by significant challenges. Key obstacles include potential genotoxicity and insertion mutation risks associated with viral vectors, immune escape driven by the complex immunosuppressive microenvironment, dense physical barriers, and antigenic heterogeneity in solid tumors. The article concludes that future research must focus on further optimizing the targeting precision and safety of delivery systems, while integrating gene editing technologies to overcome T-cell exhaustion. This approach will advance in vivo CAR-T therapy into an efficient, universal, and readily available precision treatment solution for tumors.
HUANG et al. (Mon,) studied this question.