Enforced BATF expression via clinically approved LNPs enhances adoptive T-cell therapies.

Chimeric antigen receptor (CAR) T-cell therapy is highly effective in hematologic malignancies, yet its durability is limited by insufficient expansion, persistence, and T-cell exhaustion. Basic leucine zipper ATF-like transcription factor (BATF) promotes CD8+ T-cell effector differentiation but can drive exhaustion under chronic stimulation. Here, we developed a transient, non-viral strategy to modulate BATF expression in therapeutic T cells using clinically approved lipid nanoparticles (LNPs). Among 3 Food and Drug Administration (FDA)-approved ionizable lipids, SM-102-based LNPs achieved the highest mRNA delivery efficiency in primary T cells. Transient BATF overexpression enhanced T-cell cytotoxicity in vitro without inducing exhaustion. In vivo, BATF mRNA transfection enhanced T-cell expansion, reduced exhaustion, and improved anti-tumor activity for both OT-1 TCR-T cells in melanoma and CD19 CAR-T cells in acute lymphoblastic leukemia. These findings establish a safe and reversible platform for transient transcription factor modulation to optimize T-cell differentiation and function, thereby enhancing the efficacy of adoptive T-cell therapies and supporting clinical translation.