In situ repurposing of dendritic cells with CRISPR/Cas9-based nanomedicine to induce transplant tolerance. (October 2019)

• Record Type: Journal Article
• Authors: Zhang, Yue; Shen, Song; Zhao, Gui; Xu, Cong-Fei; Zhang, Hou-Bing; Luo, Ying-Li; Cao, Zhi-Ting; Shi, Jia; Zhao, Zhi-Bin; Lian, Zhe-Xiong; Wang, Jun
• Is Part Of: Biomaterials. Volume 217(2019)
• Publication Date: 2019-10
• Subjects: CRISPR/Cas9 -- Nanoparticle -- Dendritic cell -- Gene editing -- Transplant tolerance; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2019.119302
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Organ transplantation is the only effective method to treat end-stage organ failure. However, it is continuously plagued by immune rejection, which is mostly caused by T cell-mediated reactions. Dendritic cells (DCs) are professional antigen-presenting cells, and blocking the costimulatory signaling molecule CD40 in DCs inhibits T cell activation and induces transplant tolerance. In this study, to relieve graft rejection, Cas9 mRNA (mCas9) and a guide RNA targeting the costimulatory molecule CD40 (gCD40) were prepared and encapsulated into poly(ethylene glycol)- block -poly(lactide- co -glycolide) (PEG- b -PLGA)-based cationic lipid-assisted nanoparticles (CLAN), denoted CLANmCas9/gCD40 . CLAN effectively delivered mCas9/gCD40 into DCs and disrupted CD40 in DCs at the genomic level both in vitro and in vivo . After intravenous injection into an acute mouse skin transplant model, CLANmCas9/gCD40 -mediated CD40 disruption significantly inhibited T cell activation, which reduced graft damage and prolonged graft survival. This work provides a promising strategy for reprogramming DCs with nanoparticles carrying the CRISPR/Cas9 system to abate transplant rejection.