Dual Functioned Hexapeptide‐Coated Lipid‐Core Nanomicelles Suppress Toll‐Like Receptor‐Mediated Inflammatory Responses through Endotoxin Scavenging and Endosomal pH Modulation
Excessive activation of Toll‐like receptor (TLR) signaling pathways and the circulating endotoxin are key players in the pathogenesis of many acute and chronic inflammatory diseases. Regulation of TLR‐mediated inflammatory responses by bioactive nanodevices represents a promising strategy for treati...
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Published in | Advanced science Vol. 10; no. 19; pp. e2301230 - n/a |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Germany
John Wiley & Sons, Inc
01.07.2023
John Wiley and Sons Inc Wiley |
Subjects | |
Online Access | Get full text |
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Summary: | Excessive activation of Toll‐like receptor (TLR) signaling pathways and the circulating endotoxin are key players in the pathogenesis of many acute and chronic inflammatory diseases. Regulation of TLR‐mediated inflammatory responses by bioactive nanodevices represents a promising strategy for treating these diseases. In searching for novel, clinically applicable nanodevices with potent TLR inhibitory activities, three types of hexapeptide‐modified nano‐hybrids with different cores of phospholipid nanomicelles, liposomes, and poly(lactic‐co‐glycolic acid) nanoparticles are constructed. Interestingly, only the peptide‐modified lipid–core nanomicelles (M‐P12) display potent TLR inhibitory activities. Further mechanistic studies disclose that lipid–core nanomicelles have a generic property to bind to and scavenge lipophilic TLR ligands including lipopolysaccharide to block the ligand–receptor interaction and down‐regulate the TLR signaling extracellularly. In addition, the peptide modification enables M‐P12 a unique capability to modulate endosomal acidification upon being endocytosed into macrophages, which subsequently regulates the endosomal TLR signal transduction. In an acute lung injury mouse model, intratracheal administration of M‐P12 can effectively target lung macrophages and reduce lung inflammation and injuries. This work defines a dual mechanism of action of the peptide‐modified lipid–core nanomicelles in regulating TLR signaling, and provides new strategies for the development of therapeutic nanodevices for treating inflammatory diseases.
Regulation of Toll‐like receptor (TLR)‐mediated inflammatory responses by nanodevices represents a promising strategy for treating inflammatory diseases. Herein, a generic property of lipid–core nanomicelles in endotoxin scavenging and TLR signaling modulation is discovered. Furthermore, a dual functioned hexapeptide‐coated lipid–core nanomicelle is developed to potently suppress TLR‐mediated inflammatory responses in vitro and in vivo. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2198-3844 2198-3844 |
DOI: | 10.1002/advs.202301230 |