Ex vivo pretreatment of human vessels with siRNA nanoparticles provides protein silencing in endothelial cells

Jiajia Cui, Lingfeng Qin, Junwei Zhang, Parwiz Abrahimi, Hong Li, Guangxin Li, Gregory T. Tietjen, George Tellides, Jordan S. Pober and W. Mark Saltzman ()
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Jiajia Cui: Yale University
Lingfeng Qin: Yale University School of Medicine
Junwei Zhang: Yale University
Parwiz Abrahimi: Yale University School of Medicine
Hong Li: Yale University
Guangxin Li: Yale University School of Medicine
Gregory T. Tietjen: Yale University
George Tellides: Yale University School of Medicine
Jordan S. Pober: Yale University School of Medicine
W. Mark Saltzman: Yale University

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Human endothelial cells are initiators and targets of the rejection response. Pre-operative modification of endothelial cells by small interfering RNA transfection could shape the nature of the host response post-transplantation. Ablation of endothelial cell class II major histocompatibility complex molecules by small interfering RNA targeting of class II transactivator can reduce the capacity of human endothelial cells to recruit and activate alloreactive T cells. Here, we report the development of small interfering RNA-releasing poly(amine-co-ester) nanoparticles, distinguished by their high content of a hydrophobic lactone. We show that a single transfection of small interfering RNA targeting class II transactivator attenuates major histocompatibility complex class II expression on endothelial cells for at least 4 to 6 weeks after transplantation into immunodeficient mouse hosts. Furthermore, silencing of major histocompatibility complex class II reduces allogeneic T-cell responses in vitro and in vivo. These data suggest that poly(amine-co-ester) nanoparticles, potentially administered during ex vivo normothermic machine perfusion of human organs, could be used to modify endothelial cells with a sustained effect after transplantation.

Date: 2017
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DOI: 10.1038/s41467-017-00297-x

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