Poly(lactic-<i>co</i>-glycolic acid)/Polyethylenimine Nanocarriers for Direct Genetic Reprogramming of MicroRNA Targeting Cardiac Fibroblasts

Abstract

Cardiovascular disease remains a major cause of deaths globally. Post heart infarction, the most abundant cell type of the heart, fibroblasts, undergo a series of culminating events that lead to fibrotic scar tissue. In many organisms, injury to the heart can be restored, but the adult human heart is unable to efficiently regenerate after ischemic injury. So, the inefficiency of the heart at regenerating on its own after ischemic injury accounts for its reprogramming. Herein, we demonstrate the effect of microRNAs encapsulating poly(lactic-co-glycolic acid) (PLGA)-polyethylenimine (PEI) nanocarriers for direct reprogramming of cardiac fibroblast to cardiomyocyte-like cells. Dual, cardiac-muscle-specific miRNA (miR-1 and miR-133a) polyplexes were encapsulated in biodegradable PLGA nanospheres. Cytocompatibility of the nanocomplexes were evaluated by various in vitro assays, confirming their safety profile. The change in cardiac fibroblast phenotype to cardiomyocyte was identified by the expression of late-stage signature markers. The PLGA-PEI-miRNA nanocomplex improved the intracellular internalization of cargo, exhibited pH-dependent release of the genetic material, and efficiently reprogrammed cardiac fibroblasts to cardiomyocyte-like cells. This is a first report of development of a nanovector targeting cardiac fibroblast for direct genetic reprogramming. Thus, this nanoscale approach serves as an ideal system for gene delivery and a promising therapeutic strategy for direct reprogramming of the heart.