BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Department of Respiratory Medicine, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201620, China.
BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Biomaterials. 2016 Dec;111:90-102. doi: 10.1016/j.biomaterials.2016.09.032. Epub 2016 Oct 3.
Toll-like receptor (TLR) signaling plays a central role in the pathophysiology of many acute and chronic human inflammatory diseases, and pharmacological regulation of TLR responses is anticipated to be beneficial in many inflammatory conditions. Currently there are no specific TLR inhibitors in clinical use. To overcome this challenge, we have developed a nano-based TLR inhibitor (peptide-gold nanoparticle hybrids) that inhibits a broad spectrum of TLR responses. Through mechanistic studies, we established that specific peptide decorated-gold nanoparticles that display high cellular uptake in phagocytic immune cells modulate endosomal pH, leading to significant attenuation of signaling through multiple TLRs. Using a global transcriptomic approach, we defined the broad anti-inflammatory activity of the nanoparticle in human peripheral blood mononuclear cells. In vivo studies confirmed the beneficial immunomodulatory activity since treatment with the nanoparticle significantly reduced weight loss, improved the disease activity index, and ameliorated colonic inflammation in a murine model of intestinal inflammation. This work enhances our fundamental understanding of the role of peptide coatings on the nanoparticle surface in regulating innate immune signaling, and identifies specific peptide decorated nanoparticles that may represent a novel class of anti-inflammatory therapeutics for human inflammatory diseases.
Toll 样受体 (TLR) 信号转导在许多急性和慢性人类炎症性疾病的病理生理学中起着核心作用，预计 TLR 反应的药理学调节将在许多炎症情况下有益。目前尚无特异性 TLR 抑制剂在临床应用。为了克服这一挑战，我们开发了一种基于纳米的 TLR 抑制剂（肽-金纳米粒子杂化物），可抑制广泛的 TLR 反应。通过机制研究，我们确定了在吞噬免疫细胞中具有高细胞摄取率的特定肽修饰金纳米粒子可调节内体 pH，从而显著减弱多种 TLR 的信号转导。通过全转录组学方法，我们确定了纳米粒子在人外周血单核细胞中的广泛抗炎活性。体内研究证实了其有益的免疫调节活性，因为纳米粒子的治疗显著减轻了体重减轻，改善了疾病活动指数，并改善了肠道炎症小鼠模型中的结肠炎症。这项工作增强了我们对肽涂层在调节先天免疫信号转导中的纳米粒子表面作用的基本理解，并确定了特定的肽修饰纳米粒子，它们可能代表一类用于人类炎症性疾病的新型抗炎治疗药物。
