Advances in i-motif structures: Stability, gene expression, and therapeutic applications

The i-motif, a cytosine-rich DNA structure formed under acidic conditions, plays a pivotal role in regulating gene expression and holds significant therapeutic potential across various diseases. Found in the promoter regions of oncogenes such as Bcl-2, C-MYC, and KRAS, i-motifs dynamically interact with transcription factors and ligands to modulate oncogene activity. Their pH-sensitive nature enables innovative applications, including cellular pH sensors like the “i-switch” and drug delivery platforms such as DNA hydrogels that release therapeutics in acidic tumor microenvironments. However, challenges remain in developing specific ligands and detection methods. Advances in nanotechnology and multi-target therapies highlight the transformative potential of i-motifs in precision medicine. This review underscores the importance of i-motifs as therapeutic targets and tools, bridging fundamental research with clinical applications in oncology, metabolic disorders, and neurodegenerative diseases.