Executive Summary : | Myocardial Infarction (MI) is the leading cause of death among all cardiovascular diseases with a high reoccurrence. MI is characterized by adverse effects such as cardiac cell death, loss of functionality, damaged blood vessels, and inflammation leading to cardiac hypertrophy. The treatments available are temporary and cannot influence cellular processes like apoptosis, proliferation, inflammation, and vascularization that are critical after MI. Developing a multifaceted therapy, including gene therapy that can deal with MI through multiple aspects, is an unmet need and will have a tremendous impact on the cardiac health of the individual. Several miRNAs have been reported to be involved in cardiovascular development, function, and diseases. However, numerous hurdles pose challenges in the clinical translation of miRNAs. Multiple target genes are controlled by a given miRNA, which may cause unintended consequences in off-target cells. Moreover, miRNA delivery is challenging as they are rapidly degraded by systemic nucleases, can provoke an immune response, and demonstrate very low uptake by target cells. Recently, we have reported the development of multifunctional nanoparticles (NPs) synthesized using PAMAM dendrimer (PAMAM-Histidine) [Nanomedicine, 2020, 15, https://doi.org/10.2217/nnm-2019-0363]. We showed successful delivery of miRNAs using nanocarriers to prevent hypoxia/reperfusion-induced apoptosis, critical in MI. Our miRNA-NP complexes exerted a significant anti-apoptotic effect on the H9c2 and primary rat ventricular cardiomyocytes. We reported enhanced expression of anti-apoptotic genes and decreased expression of proapoptotic genes. Further, our preliminary data suggest that selected miRNA-NPs complex can induce proliferation in the primary rat ventricular cardiomyocytes. Based on these findings, we hypothesize that NPs modified with cardiomyocyte-specific aptamers could be used for the efficient delivery of a combination of cardiac-specific miRNAs and bioactives. Thus, we propose to develop a multifaceted therapy that deals with critical cellular processes of apoptosis, proliferation, inflammation, and vascularization. This technology will result in higher proliferation and reduced apoptosis in cardiomyocytes, development of neovascularization in the myocardium, and suppression of inflammation. This will lead to the overall regeneration of the myocardium post-infarction and the prevention of recurrent MI. Therefore, cardiac remodeling will be prevented, and cardiomyocyte count will be restored, leading to increased cardiac output. We believe that their synergistic effect will lead to a novel cardiac therapy that has ever existed. |