PMID- 31271858 OWN - NLM STAT- MEDLINE DCOM- 20200923 LR - 20240104 IS - 1878-5905 (Electronic) IS - 0142-9612 (Linking) VI - 217 DP - 2019 Oct TI - In situ repurposing of dendritic cells with CRISPR/Cas9-based nanomedicine to induce transplant tolerance. PG - 119302 LID - S0142-9612(19)30401-6 [pii] LID - 10.1016/j.biomaterials.2019.119302 [doi] AB - 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 CLAN(mCas9/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, CLAN(mCas9/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. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Zhang, Yue AU - Zhang Y AD - Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, PR China; Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230027, PR China. FAU - Shen, Song AU - Shen S AD - Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China. FAU - Zhao, Gui AU - Zhao G AD - Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, PR China; Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230027, PR China. FAU - Xu, Cong-Fei AU - Xu CF AD - Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, PR China; Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, PR China. Electronic address: xucf@scut.edu.cn. FAU - Zhang, Hou-Bing AU - Zhang HB AD - Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230027, PR China. FAU - Luo, Ying-Li AU - Luo YL AD - Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, PR China; Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, 510006, PR China. FAU - Cao, Zhi-Ting AU - Cao ZT AD - Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, PR China. FAU - Shi, Jia AU - Shi J AD - Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, PR China. FAU - Zhao, Zhi-Bin AU - Zhao ZB AD - Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, PR China. FAU - Lian, Zhe-Xiong AU - Lian ZX AD - Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, PR China. FAU - Wang, Jun AU - Wang J AD - Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China; Key Laboratory of Biomedical Engineering of Guangdong Province, and Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, PR China. Electronic address: mcjwang@scut.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190624 PL - Netherlands TA - Biomaterials JT - Biomaterials JID - 8100316 RN - 0 (CD40 Antigens) RN - 0 (RNA, Guide, CRISPR-Cas Systems) RN - EC 3.1.- (CRISPR-Associated Protein 9) SB - IM MH - Animals MH - CD40 Antigens/metabolism MH - CRISPR-Associated Protein 9/*metabolism MH - CRISPR-Cas Systems/*genetics MH - Dendritic Cells/*immunology MH - Disease Models, Animal MH - Endocytosis MH - Graft Rejection/immunology MH - Graft Survival/immunology MH - Lymphocyte Activation/immunology MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - *Nanomedicine MH - RNA, Guide, CRISPR-Cas Systems/metabolism MH - Transplantation Tolerance/*immunology OTO - NOTNLM OT - CRISPR/Cas9 OT - Dendritic cell OT - Gene editing OT - Nanoparticle OT - Transplant tolerance EDAT- 2019/07/05 06:00 MHDA- 2020/09/24 06:00 CRDT- 2019/07/05 06:00 PHST- 2019/04/08 00:00 [received] PHST- 2019/06/17 00:00 [revised] PHST- 2019/06/24 00:00 [accepted] PHST- 2019/07/05 06:00 [pubmed] PHST- 2020/09/24 06:00 [medline] PHST- 2019/07/05 06:00 [entrez] AID - S0142-9612(19)30401-6 [pii] AID - 10.1016/j.biomaterials.2019.119302 [doi] PST - ppublish SO - Biomaterials. 2019 Oct;217:119302. doi: 10.1016/j.biomaterials.2019.119302. Epub 2019 Jun 24.