Giulia Di Gregorio, Coélio Vallée, Karidia Konate, Clémentine Teko-Agbo, Thania Hammoum, Héloïse Faure-Gautron, Yannick Bessin, Sebastien Deshayes, Eric Vivès, Albano C Meli, Pascal de Santa Barbara, Sandrine Faure, Stéphanie Barrère-Lemaire, Sebastien Ulrich, Prisca Boisguérin
{"title":"Enhancing WRAP-based Nanoparticles for siRNA Delivery in pH-Sensitive Environments.","authors":"Giulia Di Gregorio, Coélio Vallée, Karidia Konate, Clémentine Teko-Agbo, Thania Hammoum, Héloïse Faure-Gautron, Yannick Bessin, Sebastien Deshayes, Eric Vivès, Albano C Meli, Pascal de Santa Barbara, Sandrine Faure, Stéphanie Barrère-Lemaire, Sebastien Ulrich, Prisca Boisguérin","doi":"10.1002/cmdc.202400885","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400885"},"PeriodicalIF":3.6000,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202400885","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies.
ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs.
Contents
ChemMedChem publishes an attractive mixture of:
Full Papers and Communications
Reviews and Minireviews
Patent Reviews
Highlights and Concepts
Book and Multimedia Reviews.