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- Title
Targeted Delivery of siRNA to Macrophages for Anti-inflammatory Treatment.
- Authors
Sang-Soo Kim; Chunting Ye; Kumar, Priti; Chiu, Isaac; Subramanya, Sandesh; Haoquan Wu; Shankar, Premlata; Manjunath, N.
- Abstract
Inflammation mediated by tumor necrosis factor-α (TNF-α) and the associated neuronal apoptosis characterizes a number of neurologic disorders. Macrophages and microglial cells are believed to be the major source of TNF-α in the central nervous system (CNS). Here, we show that suppression of TNF-α by targeted delivery of small interfering RNA (siRNA) to macrophage/microglial cells dramatically reduces lipopolysaccharide (LPS)-induced neuroinflammation and neuronal apoptosis in vivo. Because macrophage/microglia express the nicotinic acetylcholine receptor (AchR) on their surface, we used a short AchR-binding peptide derived from the rabies virus glycoprotein (RVG) as a targeting ligand. This peptide was fused to nona-D-arginine residues (RVG-9dR) to enable siRNA binding. RVG-9dR was able to deliver siRNA to induce gene silencing in macrophages and microglia cells from wild type, but not AchR-deficient mice, confirming targeting specificity. Treatment with anti-TNF-α siRNA complexed to RVG-9dR achieved efficient silencing of LPS-induced TNF-α production by primary macrophages and microglia cells in vitro. Moreover, intravenous injection with RVG-9dR-complexed siRNA in mice reduced the LPS-induced TNF-α levels in blood as well as in the brain, leading to a significant reduction in neuronal apoptosis. These results demonstrate that RVG-9dR provides a tool for siRNA delivery to macrophages and microglia and that suppression of TNF-α can potentially be used to suppress neuroinflammation in vivo.
- Publication
Molecular Therapy, 2010, Vol 18, Issue 5, p993
- ISSN
1525-0016
- Publication type
Academic Journal
- DOI
10.1038/mt.2010.27