Strategies and challenges for non-viral delivery of non-coding RNAs to the heart

Non-coding RNAs (ncRNAs), such as miRNAs and long non-coding RNAs (lncRNAs) have been reported as regulators of cardiovascular pathophysiology. Their transient effect and diversified mechanisms of action offer a plethora of therapeutic opportunities for cardiovascular diseases (CVDs). However, physicochemical RNA features such as charge, stability, and structural organization hinder efficient on-target cellular delivery. Here, we highlight recent preclinical advances in ncRNA delivery for the cardiovascular system using non-viral approaches. We identify the unmet needs and advance possible solutions towards clinical translation. Finding the optimal delivery vehicle and administration route is vital to improve therapeutic efficacy and safety; however, given the different types of ncRNAs, this may ultimately not be frameable within a one-size-fits-all approach.