title: Delivery of siRNAs to Dendritic Cells Using DEC205-Targeted Lipid Nanoparticles to Inhibit Immune Responses.
abstract: Due to their ability to knock down the expression of any gene, siRNAs have been heralded as ideal candidates for treating a wide variety of diseases, including those involving "undruggable" targets. However, the therapeutic potential of siRNAs remains severely limited by a lack of effective delivery vehicles. Recently, lipid nanoparticles (LNPs) containing ionizable cationic lipids have been developed for hepatic siRNA delivery. However, their suitability for delivery to other cell types has not been determined. We have modified LNPs for preferential targeting to dendritic cells (DCs), central regulators of immune responses. To achieve directed delivery, we coated LNPs with a single-chain antibody (scFv; DEC-LNPs), specific to murine DEC205, which is highly expressed on distinct DC subsets. Here we show that injection of siRNAs encapsulated in DEC-LNPs are preferentially delivered to DEC205(+) DCs. Gene knockdown following uptake of DEC-LNPs containing siRNAs specific for the costimulatory molecules CD40, CD80, and CD86 dramatically decreases gene expression levels. We demonstrate the functionality of this knockdown with a mixed lymphocyte response (MLR). Overall, we report that injection of LNPs modified to restrict their uptake to a distinct cell population can confer profound gene knockdown, sufficient to inhibit powerful immune responses like the MLR.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Katakowski
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Mukherjee
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Wilner
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Keith E
authors.initials: KE
authors.lastname: Maier
authors.affiliation: SRI International, Menlo Park, California, USA.
authors.forename: Michael Travis
authors.initials: MT
authors.lastname: Harrison
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.|Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Teresa P
authors.initials: TP
authors.lastname: DiLorenzo
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Levy
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Palliser
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D007267:Injections; D008055:Lipids / Q000737:chemistry*; D008099:Liver / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D008055:Lipids; D034741:RNA, Small Interfering