Abstract:
:Toxins efficiently deliver cargo to cells by binding to cell surface ligands, initiating endocytosis, and escaping the endolysosomal pathway into the cytoplasm. We took advantage of this delivery pathway by conjugating an attenuated diphtheria toxin to siRNA, thereby achieving gene downregulation in patient-derived glioblastoma cells. We delivered siRNA against integrin-β1 (ITGB1)-a gene that promotes invasion and metastasis-and siRNA against eukaryotic translation initiation factor 3 subunit b (eIF-3b)-a survival gene. We demonstrated mRNA downregulation of both genes and the corresponding functional outcomes: knockdown of ITGB1 led to a significant inhibition of invasion, shown with an innovative 3D hydrogel model; and knockdown of eIF-3b resulted in significant cell death. This is the first example of diphtheria toxin being used to deliver siRNAs, and the first time a toxin-based siRNA delivery strategy has been shown to induce relevant genotypic and phenotypic effects in cancer cells.
journal_name
Sci Advjournal_title
Science advancesauthors
Arnold AE,Smith LJ,Beilhartz GL,Bahlmann LC,Jameson E,Melnyk RA,Shoichet MSdoi
10.1126/sciadv.aaz4848subject
Has Abstractpub_date
2020-05-01 00:00:00issue
18issn
2375-2548pii
6/18/eaaz4848journal_volume
6pub_type
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