Enhanced Cytoplasmic Delivery of RAGE siRNA Using Bioreducible Polyethylenimine-based Nanocarriers for Myocardial Gene Therapy

This study aims to develop bioreducible polyethylenimine (rPEI)/siRNA polyplexes with high stability, high transfection efficiency, and low cytotoxicity for efficient cytoplasmic siRNA delivery. rPEI successfully incorporated siRNA into stable and compact nanocomplexes, and the disulfide linkages in rPEI/siRNA were cleaved under reductive environments, resulting in efficient intracellular translocation and siRNA release. In this study, receptor for advanced glycation end-products (RAGE) was selected as a therapeutic target gene because it is associated with inflammatory responses in ischemia/reperfusion injury. rPEI/siRAGE exhibited high target gene silencing and low cytotoxicity in cardiomyocytes, and the treatment of rPEI/siRAGE reduced the myocardial infarction size. Bioreducible polyethylenimine (rPEI) is synthesized from low molecular weight PEI via cleavable disulfide linkages to achieve high stability, high transfection efficiency, high cytoplasmic siRNA release, and low cytotoxicity. rPEI/siRAGE polyplex can reduce RAGE expression in ischemic/reperfused myocardium, thereby leading to attenuation of myocardial infarction.