Advances in transcription factor delivery: Target selection, engineering strategies, and delivery platforms

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.