title: Endosomal pH modulation by peptide-gold nanoparticle hybrids enables potent anti-inflammatory activity in phagocytic immune cells.
abstract: 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.
authors.affiliation: 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. Electronic address: hongyang36@gmail.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kozicky
authors.affiliation: BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Aabida
authors.initials: A
authors.lastname: Saferali
authors.affiliation: BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Shan-Yu
authors.initials: SY
authors.lastname: Fung
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Afacan
authors.affiliation: BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Falsafi
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Gill
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Tobias R
authors.initials: TR
authors.lastname: Kollmann
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: R E W
authors.initials: RE
authors.lastname: Hancock
authors.affiliation: BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sly
authors.affiliation: BC Children's Hospital and Child & Family Research Institute, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada. Electronic address: sturvey@cw.bc.ca.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000276:immunology; D002478:Cells, Cultured; D011992:Endosomes / Q000737:chemistry* / Q000276:immunology*; D006046:Gold / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology*; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D053769:Nanocapsules; D058726:Nanoconjugates; D010455:Peptides; D051193:Toll-Like Receptors; D006046:Gold
keywords: Anti-inflammatory therapeutics; Immune modulation; Inflammatory bowel disease; Nanoparticle; Peptide-conjugation; Toll-like receptor signaling