Nucleic acid-based small molecules as targeted transcription therapeutics for immunoregulation.

Transcription therapy is an emerging approach that centers on identifying the factors associated with the malfunctioning gene transcription machinery that causes diseases and controlling them with designer agents. Until now, the primary research focus in therapeutic gene modulation has been on small-molecule drugs that target epigenetic enzymes and critical signaling pathways. However, nucleic acid-based small molecules have gained popularity in recent years for their amenability to be pre-designed and realize operative control over the dynamic transcription machinery that governs how the immune system responds to diseases. Pyrrole-imidazole polyamides (PIPs) are well-established DNA-based small-molecule gene regulators that overcome the limitations of their conventional counterparts owing to their sequence-targeted specificity, versatile regulatory efficiency, and biocompatibility. Here, we emphasize the rational design of PIPs, their functional mechanisms, and their potential as targeted transcription therapeutics for disease treatment by regulating the immune response. Furthermore, we also discuss the challenges and foresight of this approach in personalized immunotherapy in precision medicine.