Enhancing WRAP-based Nanoparticles for siRNA Delivery in pH-Sensitive Environments.

Abstract

SiRNA are promising therapeutic molecules that require delivery systems to reach their targets. Several siRNA delivery systems, such as lipid- or peptide-based nanoparticles, have been developed. In this context, we previously conceived a cell-penetrating peptide WRAP5 forming nanoparticles in the presence of siRNAs and validated the efficiency of this delivery system in inhibiting protein expression. In the pathophysiological context of acute myocardial infarction, which causes a pH drop in the ischemic heart tissue, we optimized the WRAP5-based nanoparticles for a pH-sensitive siRNA-targeted delivery. Therefore, pH-sensitive acyl hydrazone linkers were used to graft polyethylene (PEG) on the WRAP5 peptide. Proof of concept of the targeted delivery was performed using siRNA silencing the Fas-associated death domain (FADD) containing protein implicated in apoptosis during myocardial ischemia-reperfusion injury on two human cell models (vascular endothelial cells and hiPSC-derived cardiomyocytes). Our results show that only WRAP5 nanoparticles PEGylated via an appropriate acyl hydrazone linker with tuned pH sensitivity can induce a specific FADD knockdown at pH 5 compared to naked nanoparticles. These optimized WRAP-based nanoparticles could be a novel therapeutic tool for treating myocardial infarction by inhibiting apoptosis induced by reperfusion and maximizing local delivery of the nanoparticle content at the site of injured cells.