Mechanosensitive Non-Coding RNAs in Cardiovascular Disease: Mechanisms, Therapeutic Targeting and Cardiac Delivery

Non-coding RNAs (ncRNAs) have emerged as major regulators of gene expression and cellular homeostasis, with growing evidence supporting their involvement in cardiovascular physiology and disease. This review summarizes the classification, mechanisms of action, and functional roles of ncRNAs, with particular focus on mechano-ncRNAs involved in cardiovascular remodeling and fibrosis. Different classes of ncRNAs are discussed in relation to their contributions to vascular, valvular, and myocardial homeostasis, as well as to pathological processes including inflammation, endothelial dysfunction, and fibrotic responses. Special emphasis is placed on biomechanical stimuli, including increased matrix stiffness, cyclic strain, and altered shear stress, which can modulate ncRNA expression and activity through mechanotransduction pathways. Notable examples of mechano-ncRNAs include miR-21, miR-29, miR-132, MIAT, MALAT1, and MEG3, which have been implicated in maladaptive cardiac remodeling and fibrosis. Concurrently, we highlight the importance of technical advances in ncRNA discovery and cardiac-specific delivery systems, including viral and nanoparticle-based vectors, for the development of ncRNA-based therapeutic strategies with potential for clinical translation. Overall, ncRNAs are shown to represent promising biomarkers and therapeutic targets in cardiovascular diseases, particularly in mechanically driven pathological conditions. However, challenges related to delivery specificity, stability, off-target effects, and safety remain and will need to be addressed to enable the clinical translation of ncRNA-based therapies in precision cardiovascular medicine.