Authors: M. Aouadi, G. Tesz, E. Soto, M. Wang, S. Nicoloro, G. Ostroff, M. Czech
Affilation: University of Massachusetts Medical School, United States
Pages: 332 - 335
Keywords: oral siRNA delivery, Map4K4, inflammation
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.