Emerging strategies to reduce the side effects of CAR-T cell therapy: focusing on gene editing and nanotechnology.

CAR-T cell therapy has been transformative in treating certain blood malignancies and is also being adopted for treating other malignancies, including solid tumors. Despite its undeniable successes, CAR-T cell therapy is frequently associated with severe and potentially life-threatening side effects and toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), graft-versus-host disease (GvHD) in allogeneic settings, secondary CAR-T-derived malignancies, and long-term immunosuppression-induced risk of infections. Recent advances in integrating gene-editing technology and nanomedicine into CAR-T cell therapy have opened new avenues to enhance the safety profile of CAR-T cell therapy and broaden its clinical applications. Gene-editing tools enable targeted modulation of the CAR-T cells' genome, thereby improving their safety profile by preventing related side effects. In parallel, nanomedicine can be used at various stages, including manufacturing and post-treatment, to prevent their occurrence or manage them. This review highlights the current preclinical and clinical landscape, explores the emerging combinatorial strategies, and discusses future directions to achieve a safe and more controllable CAR-T cell therapy.