Targeting T cells in vivo: advances in non-viral gene delivery and clinical applications

T cell-targeted gene therapy has gained traction in oncology and autoimmune diseases. While viral vectors remain standard, non-viral delivery strategies are increasingly favored due to concerns over immunogenicity, safety, and complex manufacturing. This review highlights recent progress in non-viral gene delivery, focusing on in vivo targeting of T cells. Key clinical applications include in vivo generation of CAR- and TCR-T cells, T cell reprogramming within the tumor microenvironment, and interventions in autoimmune diseases. We explore emerging non-viral carriers, such as lipid nanoparticles, polymers, extracellular vesicles, and current targeting strategies. Major translational challenges, including endosomal escape, cell specificity, and protein corona effects, are discussed, alongside manufacturing and regulatory considerations. Overall, in vivo T cell-targeted gene delivery offers a versatile platform with the potential to enable personalized T cell-based therapies in the future. With ongoing improvements in efficiency, safety, and scalability, clinical adoption seems more a matter of ‘when’ than ‘if’.

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