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Several siRNA delivery systems, such as lipid\u2010 or peptide\u2010based nanoparticles, are\u00a0developed for different pathologies. In this context, we previously conceived a cell\u2010penetrating peptide WRAP5\u2010forming 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\u2010based nanoparticles for a pH\u2010sensitive siRNA\u2010targeted delivery. Therefore, pH\u2010sensitive 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\u2010associated death domain (FADD)\u2010containing protein implicated in apoptosis during myocardial ischemia\u2010reperfusion injury on two human cell models (vascular endothelial cells and hiPSC\u2010derived 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\u2010based 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.<\/jats:p>","DOI":"10.1002\/cmdc.202400885","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T08:44:06Z","timestamp":1741941846000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Enhancing WRAP\u2010Based Nanoparticles for Small Interfering Ribonucleic Acid Delivery in pH\u2010Sensitive Environments"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5349-814X","authenticated-orcid":false,"given":"Giulia","family":"Di Gregorio","sequence":"first","affiliation":[{"name":"PhyMedExp University of Montpellier, INSERM, CNRS  371 Av. 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