Recent advances in delivery systems for transcription factors (TFs) have opened new therapeutic opportunities in regenerative medicine, cancer therapy, and genetic disorders. However, effective TF delivery still faces substantial obstacles, including limited cellular uptake, inefficient nuclear translocation, low cargo stability, and insufficient target specificity. Furthermore, artificial TFs have enabled targeted modulation of gene expression, further expanding their therapeutic potential. This review comprehensively discusses current progress in TF delivery methodologies, including direct TF protein delivery using cell-penetrating peptides, and extracellular vesicles, as well as TF gene delivery approaches utilizing both lipid-based nanoparticles and viral strategies. Notably, engineered nanoparticles have emerged as promising platforms due to their precise control over TF delivery, improved specificity, and minimized off-target effects. Despite these significant advancements, major hurdles in delivery efficiency, cargo stability, and overall safety persist. Overcoming these obstacles will be essential to accelerate the clinical translation of TF-based therapeutics for a broad spectrum of diseases.

Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.