Lipidoid-siRNA Nanoparticle-Mediated IL-1β Gene Silencing for Systemic Arthritis Therapy in a Mouse Model

Ping Song; Chuanxu Yang; Jesper Skovhus Thomsen; Frederik Dagnæs-Hansen; Maria Jakobsen; Annemarie Brüel; Bent Deleuran; Jørgen Kjems

doi:10.1016/j.ymthe.2019.05.002

Lipidoid-siRNA Nanoparticle-Mediated IL-1β Gene Silencing for Systemic Arthritis Therapy in a Mouse Model

Mol Ther. 2019 Aug 7;27(8):1424-1435. doi: 10.1016/j.ymthe.2019.05.002. Epub 2019 May 15.

Authors

Ping Song¹, Chuanxu Yang², Jesper Skovhus Thomsen³, Frederik Dagnæs-Hansen³, Maria Jakobsen⁴, Annemarie Brüel³, Bent Deleuran⁵, Jørgen Kjems⁶

Affiliations

¹ Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus C, Denmark; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
² Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus C, Denmark; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: chuanxuyang@inano.au.dk.
³ Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
⁴ Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
⁵ Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark; Department of Rheumatology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
⁶ Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus C, Denmark; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: jk@mbg.au.dk.

Abstract

Interleukin-1 beta (IL-1β) plays a central role in the induction of rheumatoid arthritis (RA). In the present study, we demonstrated that lipidoid-polymer hybrid nanoparticle (FS14-NP) can efficiently deliver siRNA against IL-1β (siIL-1β) to macrophages and effectively suppress the pathogenesis of experimental arthritis induced by collagen antibody (CAIA mice). FS14-NP/siIL-1β achieved approximately 70% and 90% gene-silencing efficiency in the RAW 264.7 cell line and intraperitoneal macrophages, respectively. Intravenous administration of FS14-NP/siRNA led to rapid accumulation of siRNA in macrophages within the arthritic joints. Furthermore, FS14-NP/siIL-1β treatment lowered the expression of pro-inflammatory cytokines in arthritic joints and dramatically attenuated ankle swelling, bone erosion, and cartilage destruction. These results demonstrate that FS14-NP/siIL-1β may represent an effective therapy for systemic arthritis and other inflammatory disorders.

Keywords: IL-1β; lipidoid; nanoparticles; rheumatoid arthritis; siRNA delivery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis, Experimental
Arthritis, Rheumatoid / genetics*
Arthritis, Rheumatoid / metabolism
Arthritis, Rheumatoid / pathology
Arthritis, Rheumatoid / therapy
Biomarkers
Bone and Bones / metabolism
Bone and Bones / pathology
Cytokines / metabolism
Disease Models, Animal
Fluorescent Antibody Technique
Gene Expression
Gene Silencing*
Gene Transfer Techniques*
Genetic Therapy* / methods
Inflammation Mediators / metabolism
Interleukin-1beta / genetics*
Lipids* / chemistry
Macrophages / immunology
Macrophages / metabolism
Mice
Molecular Structure
Nanoparticles* / chemistry
Nanoparticles* / ultrastructure
RAW 264.7 Cells
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics*

Substances

Biomarkers
Cytokines
Inflammation Mediators
Interleukin-1beta
Lipids
RNA, Small Interfering