Nanotechnology-driven heart targeting to fulfil the potential of cardiac microRNA therapies

MicroRNAs play a crucial role in regulating gene expression in most biological processes, including cardiac disease, regeneration and aging. They are therefore an attractive and novel therapeutic option, and extensive research in small animal models has demonstrated this potential in the heart. While the therapeutic outcomes obtained in large animal models are also promising, far fewer studies have been conducted in this species. Even fewer microRNA therapeutics have reached clinical trials, only CDR132L and MRG-110. This highlights a bottleneck in their development primarily associated with challenges in their in vivo delivery, specifically due to their limited stability and ability to penetrate the heart tissue. This review aims to describe the current state of development of cardiac microRNA therapies in relation to these challenges and to provide a comparative overview of the progress made in overcoming them. A special focus is set on the application of pharmaceutical nanotechnology and the development of targeted delivery strategies to the heart. These approaches have been tested primarily in small animal models and have shown to improve the cardiac penetration, accumulation and/or stability and of microRNAs and, therefore, their therapeutic efficacy compared to naked delivery. Notably, the latter is typically the method of choice in late preclinical research and early clinical trials. Consequently, targeted microRNA nanotherapies could be pivotal in overcoming the current bottleneck and realizing the therapeutic potential of microRNAs in the heart. In conclusion, this review offers an outlook of the future applicability of microRNA therapies leveraging the latest advances in non-viral targeted delivery with nanocarriers.