ABSTRACT microRNAs (miRNAs) have been proven to promote cardiac regeneration after myocardial infarction. However, current miRNA delivery methods, such as viral vectors or lipid formulations, present safety concerns for widespread use. We have developed an injectable thermo-responsive hydrogel functionalized with carbon nanotubes (RTG-CNT) for the delivery of miRNAs. The RTG-CNT hydrogel transitions from a liquid-solution to a gel-based matrix shortly after reaching body temperature allowing for a liquid-based delivery rapidly followed by a stable-gel miRNA localization. Moreover, this hydrogel has improved short-term (8-week) biocompatibility compared to viral and lipid approaches and it promotes two-fold more miRNA expression than lipid formulations. In this investigation, we propose to test the hypothesis that our novel RTG-CNT hydrogel is far superior delivery model of miRNAs to the heart, through increased biocompatibility, targeted delivery and higher miRNA expression when compared to viral and lipid approaches. We will address our hypothesis with a combination of cell biology and bioengineering by 1) Quantify the biocompatibility and the magnitude of improved localization of our RTG-CNT-miRNA delivery system over liposomal and viral vectors approaches, 2) Measure the improved efficiency of the RTG-CNT hydrogel as pro-regenerative miRNA delivery system vs. liposomal and viral vector deliveries in a mouse MI model and 3) Determine the potential of the RTG-CNT hydrogel to deliver anti-fibrotic miRNAs to further improve myocardial structure and rescue function in a mouse MI model. We believe that the RTG-CNT hydrogel will offer a more biocompatible and far more efficient miRNA delivery system than traditional approaches, that can be realistically translated into clinical applications.

K25HL148386

2020-06-01

2025-05-31