Polymer-Based DNA Delivery Nanoplatforms for Chimeric Antigen Receptor T Cells Engineering

Although chimeric antigen receptor (CAR) T cell therapy represents a groundbreaking advancement in cancer treatment, its widespread application is hindered by high costs and complex protocols associated with the current gene delivery systems used for CAR T cell production. This study introduces an innovative, cost-effective, nonviral polymeric nanosystem for ex vivo delivery of a leukemia-targeting anti-CD19 CAR gene (used as a model) to T cells. Using cationic polymers, specifically poly[(2-dimethylamino)ethyl methacrylate] (PDMAEMA) and poly(β-amino ester) (PβAE), we developed various formulations through straightforward processes. Notably, star-shaped PDMAEMA/PβAE-based polyplexes exhibit favorable physicochemical properties as gene delivery platforms and demonstrate remarkable efficiency in CAR gene delivery with minimal toxicity due to enhanced internalization and effective endosomal escape. Our best nanosystem formulation successfully generated CAR T cells that effectively target and induce leukemia cell death. Overall, this approach simplifies manufacturing and reduces costs of CAR T cell engineering, paving the way for more accessible and effective cell therapies against cancer.