SiRNA-loaded Biodegradable Lipid Nanoparticles Ameliorate Concanavalin A-induced Liver Injury

Overview

Journal Mol Ther Nucleic Acids

Publisher Cell Press

Date 2021 Sep 30

PMID 34589288

Citations 6

Authors

Wataru Kawase

Daisuke Kurotaki

Yuta Suzuki

Hiroshi Ishihara

Tatsuma Ban

Go R Sato

Juri Ichikawa

Hideyuki Yanai

Tadatsugu Taniguchi

Kappei Tsukahara

Tomohiko Tamura

Affiliations

Soon will be listed here.

Abstract

RNA interference-based gene silencing drugs are attracting attention for treating various diseases. Lipid nanoparticles (LNPs) are carriers that efficiently deliver small interfering RNA (siRNA) to the cytoplasm of target cells. Recently, we developed potent and well-tolerated biodegradable LNPs with asymmetric ionizable lipids. Here, we evaluated the effect of LNPs on immune cells in mice. After intravenous administration, LNPs were efficiently incorporated into several tissue-resident macrophages, including liver macrophages, through an apolipoprotein E (ApoE)-independent mechanism. Administration of LNP-encapsulated siRNA against , encoding the transcription factor critical for inflammatory responses, sharply reduced its expression in macrophages , and persisted for as long as 7 days. The therapeutic potential of siRNA-loaded LNPs in inflammatory diseases was tested in a concanavalin A (Con A)-induced hepatitis model, whose pathogenic mechanisms are dependent on cytokine secretion from macrophages. We found that Con A-induced liver injury was significantly attenuated after LNP injection. Serum aspartate transaminase, alanine aminotransferase, and inflammatory cytokine levels were significantly reduced in mice injected with siRNA-loaded LNPs compared to those injected with control siRNA-loaded LNPs. Our results suggest that administering biodegradable LNPs to deliver siRNA is a promising strategy for treating inflammatory disorders.

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