Strategies for the delivery of RNA therapeutics to diseased heart tissue

Cardiovascular diseases (CVDs) account for one-third of the global mortality rate. RNA therapeutics have emerged as promising tools to modulate gene expression and molecular pathways in CVDs. However, their clinical translation is hampered by instability, immunogenicity, and inefficient delivery across anatomical and physiological barriers. This review critically examines emerging strategies for the targeted delivery of RNA therapeutics to the heart, critically analyzing systemic and local barriers. Emphasis is placed on chemical modifications of RNA molecules, encapsulation, biomimetic, and targeted approaches to enhance tissue and cellular targeting. The analysis is supported by a structured literature search encompassing preclinical and translational studies. Challenges to the clinical translation of RNA delivery are highlighted. Research and review articles, as well as clinical trials published between 2008 and 2024 were searched from PubMed, Web-of-Science, and ClinicalTrials.gov. Local delivery systems are crucial to improve RNA retention and diffusion through the extracellular matrix (ECM), while cell-type - specific strategies targeting cardiomyocytes and fibroblasts can enhance precision within the heterogeneous cardiac microenvironment (CME). These approaches represent a fundamental basis for the rational design of RNA therapeutics to overcome biological barriers and enable efficient, targeted delivery to cardiac tissue.