Oral Delivery of Map4K4 siRNA to Macrophages Inhibits TNF alpha Production and Protects against a LPS-Galactosamine Challenge in Mice

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RNA interference (RNAi) is a new, promising approach to selectively regulate gene expression through modulating mRNA stability and translation. However, the efficient delivery of 21 mer dsRNA molecules (siRNA) to affect RNAi remains a challenge. Here we report on the development of a new delivery technology based on the in situ layer by layer synthesis of siRNA containing nanoplexes encapsulated within hollow yeast cell wall particles (YCWP). YCWP provide for receptor-mediated oral bioavailability and macrophage targeting of nanoplexed cargos, such as siRNA. We have identified a mitogen-activated protein kinase (Map4K4) that controls adipocyte signaling (PNAS 14; 103(7): 2087–2092 2006). In addition, Map4K4 controls TNFalpha expression in macrophages in response to an LPS challenge. siRNA targeting Map4k4 formulated in YCWP and administered to C57BL/6J mice (10 ug siRNA/Kg) by intraperitoneal or oral routes for 8 days effectively knocked down Map4K4 and TNF mRNA levels (>50%) in murine peritoneal exudate cells, and in splenic and liver macrophages compared to a YCWP delivered scrambled siRNA control. Mice orally pretreated with YCWP encapsulated Map4K4 siRNA (10 ug siRNA/Kg) for 8 days were significantly protected against an LD90 challenge of LPS-Galactosamine. These results demonstrate the efficient in vivo YCWP-mediated delivery of siRNA by both systemic and oral routes and the utility of targeting Map4K4 to modulate inflammatory processes.

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Journal: TechConnect Briefs
Volume: 2, Nanotechnology 2008: Life Sciences, Medicine & Bio Materials – Technical Proceedings of the 2008 NSTI Nanotechnology Conference and Trade Show, Volume 2
Published: June 1, 2008
Pages: 332 - 335
Industry sector: Medical & Biotech
Topics: Biomaterials, Materials for Drug & Gene Delivery
ISBN: 978-1-4200-8504-4