Directly Generate CAR-T Cells In Vivo to Safely And Effectively Treat Cancer

Researchers from South China University of Technology published a research paper titled "Leveraging T cell-specific fusogenicity of HIV for in vivo mRNA delivery to produce human CAR-T cells" in Cell Biomaterials, a subsidiary of Cell. The study used the T cell-specific fusion of HIV virus to develop a T cell-specific fusion virus-like particle (T-FVLP) that can mimic HIV virus and efficiently deliver CAR mRNA into T cells, thereby producing human CAR-T cells in vivo.

Mouse model experiments showed that T-FVLP_mCAR can generate enough CAR-T cells in vivo and effectively treat lymphoma. And it does not cause side effects such as cytokine release syndrome and neurotoxicity, thus providing a scalable and safer alternative to traditional CAR-T production.

Human immunodeficiency virus (HIV) is the virus that causes AIDS in humans. It is an RNA virus composed of an envelope, a capsid, and RNA, and can infect human CD4+ T cells. The envelope glycoprotein gp160 on HIV virus can recognize CD4 molecules on T cells, thereby promoting the fusion of the viral envelope with the T cell membrane. This process enables the genomic RNA loaded by the capsid protein gag to be delivered directly to the cytoplasm of T cells, thereby bypassing the endocytosis pathway. In addition, studies have confirmed that a mutant gp160 can target CD4+ and CD8+ T cells, which expands the targeting potential for different T cell subsets.

Therefore, HIV is a natural RNA drug carrier with a unique delivery method, which can specifically and efficiently deliver RNA to T cells through a cell-targeted membrane fusion mechanism. In this new study, the research team used the membrane fusion mechanism of HIV virus to design a T cell-specific fusion virus-like particle (T-FVLP) that can mimic HIV virus and efficiently deliver CAR mRNA into T cells (T-FVLP_mCAR), thereby generating human CAR-T cells in vivo.

Figure 1. Engineering T-FVLP with T cell-specific membrane fusion capability. (Wang Y, et al., 2025)

T-FVLP_mCAR displays a mutant envelope glycoprotein gp160 on its surface and loads CAR mRNA through the capsid protein Peg10. Mutant gp160 can specifically recognize human T cells and initiate the fusion of T-FVLP_mCAR with the T cell membrane, thereby delivering CAR mRNA directly to the cytoplasm of T cells to generate human CAR-T cells.

Systemic injection of T-FVLP_mCAR per mouse requires less than 1 microgram of anti-CD19 CAR mRNA to produce enough CAR-T cells in mice to treat B cell lymphoma. And it does not cause side effects such as cytokine release syndrome and neurotoxicity.

Overall, this study developed a T-FVLP_mCAR that mimics the active recognition and membrane fusion mechanism of HIV and can efficiently and specifically deliver CAR mRNA to human T cells. This strategy enables the generation of transient human CAR-T cells in vivo, thereby improving the efficiency and safety of CAR-T cell therapy.