The silencing of indoleamine 2,3-dioxygenase 1 (IDO1) in dendritic cells by siRNA-loaded lipid nanoparticles enhances cell-based cancer immunotherapy

Abstract

Cell-based therapy using dendritic cells (DC) represents a potent cancer immunotherapy. However, activated DC express indoleamine 2,3-dioxygenase 1 (IDO1), a counter-regulatory and tolerogenic molecule, leading to the inhibition of T cell activation and the promotion of T cell differentiation into regulatory T cells. Silencing the IDO1 gene in DC by small interfering RNA (siRNA) represents a potent therapeutic strategy. We report on the successful and efficient introduction of a siRNA targeting IDO1 into mouse DCs by a means of a multifunctional envelope-type nanodevice (MEND) containing a YSK12-C4 (YSK12-MEND). The YSK12-C4 has both fusogenic and cationic properties. The YSK12-MEND induced an effective level of gene silencing of IDO1 at siRNA doses in the range of 1–20 nM, a concentration that commercially available transfection reagents are not able to silence. The YSK12-MEND mediated IDO1 silencing had no effect on the characteristic determinants of DC phenotype such as CD11c, CD80 and MHC class II. The silencing of IDO1 in DC by the YSK12-MEND significantly enhanced the antitumor effect against E.G7-OVA tumor. Moreover, a decrease in the numbers of regulatory T cells in the tumor was observed in mice that were treated with the IDO1-silenced DC. The YSK12-MEND appears to be a potent delivery system for IDO1-silenced DC based cancer immunotherapy.

Silencing of Exosomal miR-181a Reverses Pediatric Acute Lymphocytic Leukemia Cell Proliferation

“…Other groups have attempted exosomal silencing by siRNA with similar results; i.e., exosomal delivery of a PLK-1 gene-specific siRNA silencer in UMUC3 bladder cancer cell lines showed >60% silencing of PLK-1 expression [43]. Endo et al used a lipid nanoparticle as delivery system carrying siRNA (90% encapsulation of siRNA into the lipid nanoparticle) for the silencing of indoleamine2, 3 dioxygenase 1 gene which has implications for cancer immunotherapy [30]. However, exosome-based siRNA-inhibitor delivery can be considered a better vehicle system than liposomal-based or other vector delivery systems for several reasons: (1) Exosomes are biological nano-carrier systems that easily communicate with target cells for exosomal cargo delivery.…”

“…Endo et al demonstrated that cellular gene silencing by lipid nanoparticles, loaded with a gene-specific siRNA, significantly downregulated the expression of indoleamine 2, 3-dioxygenase 1. This study provides a proof-of-concept that microvesicles can be exploited as vehicles and/or delivery systems for siRNA [30].…”

Evolution of drug delivery system from viewpoint of controlled intracellular trafficking and selective tissue targeting toward future nanomedicine

“…However, it is well known that it is difficult to introduce siRNA to immune cells using non-viral vectors. We previously developed siRNA-loaded LNPs that target various immune cells [ [131] , [132] , [133] , [134] , [135] , [136] ]. An LNP composed of YSK12-C4, a cationic lipid with fusogenic capability, efficiently introduced siRNA to mouse DCs and to human immune cell lines (Jurkat, THP-1, KG-1 and NK-92) compared with commercially available siRNA transfection reagents [ 133 , 134 , 136 ].…”

Silencing of Exosomal miR-181a reverses Pediatric Acute Lymphocytic Leukemia Cell Proliferation

“…exosomal delivery of a PLK-1 gene-specific siRNA silencer in UMUC3 bladder cancer cell lines showed >60% silencing of PLK-1 expression 45 . Endo et al showed lipid nanoparticle as delivery system carrying siRNA (90% encapsulation of siRNA into the lipid nanoparticle) for the silencing of indoleamine2, 3 dioxygenase 1 gene which has implication for cancer immunotherapy 46 .…”

“…Silencing of miRNA/mRNA at cellular level is widely accepted and most commonly performed in scientific communities, but silencing at lipid nanoparticle/exosomes level are not common yet, its emerging. A recent article demonstrated cellular gene (indoleamine2, 3-dioxygenase 1) silencing by lipid nanoparticle loaded with gene specific siRNA showed significant effect by downregulatingindoleamine2, 3-dioxygenase 1, which showed lipid nanoparticle is vehicle/delivery system for siRNA 46 .…”