Advances in i-motif structures: Stability, gene expression, and therapeutic applications
Mengqing Wu, Yang Liu, Xiao Zhu, Xiaoke Zhang, Qinghong Kong, Wei Lu, Xiao Yuan, Yunlai Liu, Yang Liu, Keyu Lu, Yangxue Dai, Bo Zhang
Abstract
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.