The paradox of nuclear miRNAs: Mechanisms, therapeutic potential, and future directions

Nuclear microRNAs represent a novel class of non-canonical miRNAs localized within the nucleus, distinguished from classical cytoplasmic miRNAs by their unique ability to activate gene transcription. Classical miRNAs, approximately 22 nucleotides in length, regulate target mRNA stability or translational efficiency, primarily leading to translation inhibition or mRNA degradation. In contrast, nuclear microRNAs, measuring 18-22 nucleotides, do not rely on Dicer processing and are directly cleaved from precursor miRNAs by Drosha. Their nuclear localization and regulation of gene transcription contrast sharply with the suppressive role of classical miRNAs. Nuclear microRNAs are transcribed and modified within the nucleus via RNA polymerase II, undergoing processing similar to conventional miRNAs but diverging in their final nuclear localization and functional mechanisms. They interact with key regulatory elements such as promoters, enhancers, or gene bodies, modulating gene expression at the transcriptional level. This interaction can occur through RNA-RNA scaffolding, RNA-DNA hybrid formation, or RNA-DNA triplex formation, influencing chromatin structure and transcription factor accessibility. Nuclear microRNAs demonstrate diverse regulatory functions, acting as enhancer triggers, promoter regulators, and transcriptional amplifiers. They recruit transcription factors or alter chromatin's epigenetic state to promote transcription, impacting cellular processes such as hematopoiesis, differentiation, and apoptosis. In particular, nuclear microRNAs have been implicated in cancer progression and therapeutic responses, with the potential to orchestrate oncogene networks and tumor-suppressive pathways. Despite their promising therapeutic potential, clinical translation of nuclear microRNAs faces challenges such as delivery precision, immunogenicity, regulatory complexity, and ethical governance. Advancing nuclear delivery systems and mechanistic studies are essential to overcome these limitations and harness the full potential of nuclear microRNAs in gene regulation therapeutics. As research progresses, nuclear microRNAs may revolutionize RNA therapeutics by enabling transcriptional-level disease intervention.