In vivo production of CAR-T cells using virus-mimetic fusogenic nanovesicles

作者：Zhao, Gui; Zhang, Yue; Xu, Cong-Fei^*; Wang, Jun^*

来源：Science Bulletin, 2024, 69(3): 354-366.

DOI：10.1016/j.scib.2023.11.055

• CAR-T
• Nanovesicle
• Fusogen
• Cancer immunotherapy

Engineered T cells expressing chimeric antigen receptor (CAR) exhibit high response rates in B-cell malignancy treatments and possess therapeutic potentials against various diseases. However, the complicated ex vivo production process of CAR-T cells limits their application. Herein, we use virus-mimetic fusogenic nanovesicles (FuNVs) to produce CAR-T cells in vivo via membrane fusion-mediated CAR protein delivery. Briefly, the FuNVs are modified using T-cell fusogen, adapted from measles virus or reovirus fusogens via displaying anti-CD3 single-chain variable fragment. The FuNVs can efficiently fuse with the T-cell membrane in vivo, thereby delivering the loaded anti-CD19 (aCD19) CAR protein onto T-cells to produce aCD19 CAR-T cells. These aCD19 CAR-T cells alone or in combination with anti-OX40 antibodies can treat B-cell lymphoma without inducing cytokine release syndrome. Thus, our strategy provides a novel method for engineering T cells into CAR-T cells in vivo and can further be employed to deliver other therapeutic membrane proteins.