Mustafa Korkutata, Nihat Dilsiz
Insomnia is a multifactorial disorder characterized by persistent sleep disturbances arising from complex interactions among genetic, epigenetic, environmental, and neurophysiological factors. Recent advances in neuroepigenetics show that abnormal DNA methylation, histone modifications, and dysregulation of microRNAs (miRNAs) contribute significantly to circadian misalignment, stress response, and hyperarousal, which are central to the development of insomnia. Meanwhile, mesenchymal stem cell-derived exosomes (MSC-Exos) are emerging as promising tools for precise drug delivery because of their biocompatibility, ability to cross the blood-brain barrier, and natural molecular cargo, especially miRNAs that can influence sleep-related gene expression. In this narrative review, we integrate current insights into how epigenetic mechanisms, including non-coding RNAs, histone modifications, and DNA methylation, modulate sleep-wake homeostasis and the circadian clock. We also discuss the potential of modified MSC-Exos for diagnosis and treatment, including targeting sleep circuits and delivering biomarkers. In addition, we highlight the role of artificial intelligence and multi-omics data integration as promising approaches for classifying insomnia subtypes and predicting outcomes. By connecting advances in sleep epigenetics, exosome engineering, and systems medicine, this overview provides a foundation for developing personalized, non-invasive treatments for insomnia and related circadian disorders.