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>Gemini lipid nanoparticle (GLNP)-mediated oral delivery of TNF-α siRNA mitigates gut inflammation via inhibiting the differentiation of CD4+ T cells
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Gemini lipid nanoparticle (GLNP)-mediated oral delivery of TNF-α siRNA mitigates gut inflammation via inhibiting the differentiation of CD4+ T cells
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机译:Gemini 脂质纳米颗粒 (GLNP) 介导的 TNF-α siRNA 口服递送通过抑制 CD4+ T 细胞的分化来减轻肠道炎症
Proinflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) are critical mediators of inflammatory bowel disease pathogenesis, and are important targets to restore intestinal homeostasis. Herein, we present the engineering and screening of gemini lipid nanoparticles (GLNPs) for siRNA delivery to colon epithelial cells, macrophages and dendritic cells, and their ability to deliver siRNA therapeutics to the inflamed gastrointestinal tract. We synthesized eight gemini cationic lipids by tethering two lithocholic acid molecules through 3′-hydroxyl- and 24′-carboxyl-derived ammonium groups using different polyalkylene spacers. Screening of GLNPs, composed of gemini cationic lipid and dioleoylphosphatidylethanolamine lipid, showed that GLNPs derived from gemini lipid G1 are the most effective in the delivery of siRNA across mammalian cell membranes with reduced toxicity. Gemini lipid G1-derived siRNA–GLNP complexes (siGLNPs) can effectively reduce gene expression, and are stable in simulated gastric fluid. The delivery of TNF-α siRNA using siGLNPs can mitigate gut inflammation in a dextran sodium sulfate-induced murine inflammation model. As CD4+ T cells, especially Th17 cells, are key mediators of gut inflammation, we further showed that these siGLNPs inhibit infiltration and differentiation of CD4+ T cells to Th17 and Treg cells. Therefore, this study highlights the potential of GLNPs derived from lithocholic acid-derived gemini cationic lipids for the development of next-generation nucleic acid delivery vehicles.
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