Designer amphiphilic helical peptide-decorated nanomicelles enable simultaneous inflammation control and triple-destruction of bacteria for treating bacterial pneumonia and sepsis.
Sixia Liu, Rui Wang, Lian Li, Xiaohuan Wang, Jiameng Gong, Xingzu Liu, Zichen Song, Liya Sun, Xiali Liu, Wen Ning, Yuanlin Song, Shan-Yu Fung, Hong Yang
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引用次数: 0
Abstract
Multifunctional nanodevices that simultaneously destruct bacteria and control detrimental inflammation are anticipated to serve as an effective therapy for sepsis. Toll-like receptor 2 (TLR2) and TLR4 signaling pathways are pivotal to the pathogenesis of sepsis from the clinical data analysis. Herein, inspired by understanding of the molecular interactions between TLR2/4 and their natural ligands, we de novo design an amphiphilic, helical, cationic peptide R18, which potently inhibits the activation of both TLR2 and TLR4, and eradicates bacteria. Such inhibition is primarily achieved by binding of R18 to TLR2 or to both TLR4 ligand and receptor, which interferes with the ligand-receptor interactions. We also define the essential role of the hydrophobic and cationic amino acid residues in the peptide sequence in these multi-actions. By conjugating R18 to the self-assembled PEGylated phospholipid-based nanomicelles (designated as M-CR18), the antibacterial activity and the stability are significantly enhanced. The mechanistic studies reveal that M-CR18 effectively eliminates bacteria through triple-destruction on bacterial membrane integrity, biofilm formation, and bacterial flagellar assembly when compared with the molecular R18. The in vivo efficacy of M-CR18 is validated in infectious mouse models of cecal ligation and puncture as well as Pseudomonas aeruginosa-induced acute lung injury, and a non-infectious mouse model of lipopolysaccharide (LPS)-induced pulmonary inflammation. Finally, M-CR18 can effectively eliminate clinically present drug-resistant bacteria. This study provides a de novo design principle for multifunctional nanodevices with immunomodulatory and antibacterial activities, which represent a novel class of nano-antibiotics for the treatment of bacterial infection-mediated pneumonia and sepsis.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.