[HTML][HTML] Targeted delivery of siRNA to macrophages for anti-inflammatory treatment

SS Kim, C Ye, P Kumar, I Chiu, S Subramanya, H Wu… - Molecular therapy, 2010 - cell.com
SS Kim, C Ye, P Kumar, I Chiu, S Subramanya, H Wu, P Shankar, N Manjunath
Molecular therapy, 2010cell.com
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 …
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.
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