DNA-Based Nanocarriers to Sequester Altered microRNAs in Cardiac Dysfunction

Abstract

MicroRNAs (miRs) play a critical role in modulating gene expression across biological processes, including cardiac aging and disease. As such, miRs have demonstrated therapeutic potential in several cardiac conditions. Efficient delivery of miR therapies to cardiac tissue is crucial for effective gene therapy and DNA-based nanocarriers (DNCs), based on Watson-Crick-Franklin highly specific base-pair recognition, have emerged as a promising, biocompatible alternative to viral-based methods. Here, DNCs designed to modulate miR levels as a potential treatment for cardiac dysfunction are presented. Specifically, the DNCs target miR-24-2, which inhibits SERCA2 gene. In humans, the reduction of SERCA2 activity is a hallmark of heart failure and is altered in cardiac aging. The assembled DNCs bearing anti-miR-24-2-5p sequences effectively restore intracellular levels of SERCA2 in a HEK293 cell model. The DNCs proper assembly is thoroughly verified, while their stability and miR-capture ability are demonstrated in vitro. The DNCs exhibit successful internalization into HEK293 and modest uptake into human cardiomyocytes. SERCA2 restoration by DNCs is significantly influenced by the miR-capture sequence layout, underscoring the importance of precise design for optimal biological outcomes. This study highlights the potential of DNCs in cardiac therapies, a previously unexplored avenue for addressing cardiac dysfunction.