Promoter‐Targeting <scp>RNA</scp> Technologies: An Epigenetic Strategy for Gene Activation and Gene Silencing

Promoter-targeted RNAs (PTRs) are emerging as a transformative approach for future therapeutics, offering the ability to directly modulate gene expression at the transcriptional level. Unlike traditional RNA-based methods that work post transcriptionally, PTRs interact with gene promoter regions to either activate or suppress gene transcription. This strategy offers a key advantage by enabling more stable and long-lasting control of gene expression, since it acts directly at the level of chromatin and epigenetic regulation rather than only degrading RNA or blocking translation. Unlike CRISPR-based methods, promoter-targeted RNAs alongside traditional siRNAs and ASOs provide a reversible and finely tuned way to reprogram the chromatin accessibility and histone modifications without making permanent changes to the genome. This review explores the broadening spectrum of PTRs modalities, including small activating RNAs, small interfering RNAs, promoter-targeted R-loop inducers, peptide nucleic acids, RNA aptamers, and triplex-forming RNAs. Several preclinical studies have demonstrated their ability to reactivate silenced tumor suppressor genes or downregulate oncogenes, offering targeted and reversible gene control. Notably, saRNAs like MTL-CEBPA (Phase II) and RAG-01 (Phase I) have reached clinical evaluation for liver and bladder cancer, highlighting their translational potential. However, efficient nuclear delivery, off-target effects, immune activation, and tumor heterogeneity remain the major concerns for clinical applications. Future progress in this field will depend on overcoming technical hurdles such as ensuring efficient nuclear delivery, improving chemical modifications to increase RNA stability, and designing delivery systems that combine tissue-specific targeting with precise transcriptional regulation. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.