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.