Dual Functioned Hexapeptide-Coated Lipid-Core Nanomicelles Suppress Toll-Like Receptor-Mediated Inflammatory Responses through Endotoxin Scavenging and Endosomal pH Modulation
- Adv Sci (Weinh). 2023 Apr 20;e2301230. doi: 10.1002/advs.202301230.
- 1. The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Sciences, Intensive Care Unit of the Second Hospital, Tianjin Medical University, No. 22 Qixiangtai Road, Heping district, Tianjin, 300070, China.
- 2. Department of Immunology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping district, Tianjin, 300070, China.
- 3. Department of Pulmonary and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Shanghai, 201620, China.
- 4. Intensive Care Unit of the Second Hospital, Tianjin Medical University, No. 22 Qixiangtai Road, Heping district, Tianjin, 300070, China.
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.