In Vivo CAR-T cell engineering delivers chimeric antigen receptor (CAR) molecules transgenes directly to endogenous T cells using lentiviral vectors or targeted lipid nanoparticles, bypassing the manufacturing processes of ex vivo cellular therapies. Lentiviral vectors provide integration-based expression for sustained tumor control, whereas lipid nanoparticles enable transient, repeat-dosable therapies for autoimmune disease. First-in-human clinical trials have confirmed proof-of-concept: CAR-T cells expand, deplete target cells, and generate clinical responses, including negative minimal residual disease in multiple myeloma and induce B-cell depletion in systemic lupus erythematosus. However, persistence remains substantially shorter than ex vivo CAR T cell products. This review presents platform architecture, preclinical data, and emerging clinical evidence. We propose a Quality-by-Design (QbD) framework-a systematic, science- and risk-based development approach that begins with predefined product objectives and links critical quality attributes to material attributes and process controls- integrating vector pharmacology with immune parameters and discuss development pathways that emphasize platform–indication matching, innate immune evasion, and adjunctive T-cell conditioning to address the persistence gap and safety control.



