期刊
NATURE
卷 458, 期 7242, 页码 1180-U116出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature07774
关键词
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资金
- The University of Massachusetts Diabetes and Endocrinology Center [DK 32520]
- Diabetes Genome Anatomy Project [DK 60837]
- Commonwealth Medicine
- NIH [DK 30898]
Gene silencing by double-stranded RNA, denoted RNA interference, represents a new paradigm for rational drug design(1). However, the transformative therapeutic potential of short interfering RNA ( siRNA) has been stymied by a key obstacle-safe delivery to specified target cells in vivo(2). Macrophages are particularly attractive targets for RNA interference therapy because they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes(3). Here we report the engineering of beta 1,3-D-glucan-encapsulated siRNA particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo. Oral gavage of mice with GeRPs containing as little as 20 mu g kg(-1) siRNA directed against tumour necrosis factor alpha (Tnf-alpha) depleted its messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum Tnf-a levels. Screening with GeRPs for inflammation genes revealed that the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) is a previously unknown mediator of cytokine expression. Importantly, silencing Map4k4 in macrophages in vivo protected mice from lipopolysaccharide-induced lethality by inhibiting Tnf-alpha and interleukin-1 beta production. This technology defines a new strategy for oral delivery of siRNA to attenuate inflammatory responses in human disease.
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