Nanotechnology for next-generation CAR T-Cell manufacturing

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape of hematological malignancies; however, its broader clinical implementation remains constrained by the complexity, cost, and variability of current manufacturing workflows. Conventional CAR T-cell production relies on multistep ex vivo processes including T-cell activation, genetic engineering, expansion, and quality control, each of which influences the phenotype, persistence, and therapeutic efficacy of the final cellular product. Increasing evidence indicates that manufacturing is not merely a logistical process, but a critical biological determinant of CAR T-cell function. Consequently, the field is undergoing a conceptual transition from maximizing expansion and transduction toward actively engineering therapeutically favorable cellular states. Recent advances in nanotechnology and biomaterials engineering provide unprecedented opportunities to address these challenges through precise control of biochemical, spatial, and mechanical cues governing T-cell behavior. This review discusses emerging nanotechnology-enabled strategies across the complete CAR T-cell manufacturing pipeline. The review examines engineered activation platforms that exploit substrate stiffness, topography, ligand organization, and mechanobiological signaling to tune T-cell activation, differentiation, and exhaustion. It further discusses nanotechnology-based approaches for improving viral transduction and enabling non-viral CAR delivery through lipid nanoparticles, nanostructured interfaces, and intracellular delivery systems. Emerging strategies for engineering expansion microenvironments designed to preserve stem-like and memory phenotypes, as well as in vivo CAR generation strategies that may bypass conventional ex vivo manufacturing altogether, are then highlighted. Finally, we highlight nanoscale biosensing and analytical platforms that enable real-time manufacturing monitoring, quality control and adaptive process optimization. Collectively, these advances position nanotechnology as a transformative platform for next-generation CAR T-cell manufacturing.