Nanomedicine for Cardiovascular Disorders

stroke Repair of infarcted myocardium with improved miRNA delivery system Evaluation of: Yang H, Qin X, Wang H et al.An in vivo miRNA delivery system for restoring infarcted myocardium.ACS Nano 13(9), 9880-9894 (2019) -written by I Cicha.Cardiovascular disease remains the leading cause of death worldwide, being responsible for 31% of all global deaths [1].In the EU, there were more than 3 million new cases of ischemic heart disease in 2015 [2].In the USA, coronary events are expected to occur in about 1,055,000 individuals in 2019, including 720,000 new and 335,000 recurrent coronary events [3].Coronary atherothrombosis leading to myocardial infarction (MI) requires effective therapeutic intervention to prevent heart failure, but the currently available strategies do not induce cardiac tissue repair.In their paper, Yang et al. address the problem of ineffective delivery of therapeutic miRNA to the infarcted myocardium.To improve the safety and efficacy of in vivo delivery, the authors designed polymer-based nanoparticles, composed of a PFBT core (poly[9,9-dioctylfluorene-alt-benzothiadiazole]), which has a good biocompatibility and stable fluorescence that allows accurate tracking of the particles, and a DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly[ethylene glycol]) shell, which improves stability and protects the conjugated small interfering RNA from enzymatic degradation.Furthermore, the functional groups of DSPE-PEG were functionalized with TAT peptide, a cell-penetrating peptide derived from the transactivator of transcription (TAT) of human immunodeficiency virus and used to overcome the lipophilic barrier of the cellular membranes to deliver cargo inside the cell.As a therapeutic agent, miR-199a-3p was selected, which is capable of triggering the cell-cycle re-entry of rat and mouse adult/neonatal cardiomyocytes [4] and inducing their proliferation.The produced nanoparticles, termed miNPs, were characterized in terms of physico-chemical properties and stability.miNPs had a hydrodynamic size of approximately 110 nm and a zeta potential of 22 mV.The cytotoxicity of miNPs was very low in the human embryonic stem cell-derived cardiomyocytes (CM) and endothelial cells (ECs) even at high miRNA loading concentrations (100 nM for CMs, 50 nM for ECs) in comparison with the transfection agent lipofectamine, indicating a negligible risk of damage to human cardiovascular cells.Due to the presence of cell-penetrating peptide, more than 60% of miNPs were internalized into the human cardiovascular cells with extremely low leakage.In vitro, miNP activated the cell-cycle re-entry of CMs and ECs and induced the HIF-1/VEGF pathway, which can contribute to improved cardiac function post-MI.The authors therefore investigated whether in vivo delivery of miNP restores cardiac function in a rat model of ischemia/reperfusion (MI model).To improve the local delivery, they employed the miNPs suspended within a shear-thinning hydrogel based on elastin-like protein-hyaluronic acid, which was injected directly into the beating rat hearts.In the hydrogel/miNP group, the contraction of the left ventricle was significantly maintained over 3 months as compared with rats treated with hydrogel only, miNP only or hydrogel/miNP-scramble.CM proliferation in the infarct zone and the capillary growth in the border zone were also enhanced in animals treated with hydrogel/miNP, suggesting that miRNA interference caused heart muscle regeneration and the activation of angiogenesis, leading to improved restoration of cardiac function.