Enhancing WRAP‐Based Nanoparticles for Small Interfering Ribonucleic Acid Delivery in pH‐Sensitive Environments

Small interfering RNAs (siRNA) are promising therapeutic molecules that require delivery systems to reach their targets. Several siRNA delivery systems, such as lipid- or peptide-based nanoparticles, are developed for different pathologies. In this context, we previously conceived a cell-penetrating peptide WRAP5-forming nanoparticles in the presence of siRNAsand 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 are used to graft polyethylene (PEG) on the WRAP5 peptide. Proof of concept of the targeted delivery is 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). The results show that only PEGylated WRAP5 nanoparticles via an appropriate acyl hydrazone linker 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.