设计的两亲性螺旋肽装饰纳米胶束可以同时控制炎症和三重破坏细菌,用于治疗细菌性肺炎和败血症。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.110538
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

摘要

多功能纳米装置可同时杀灭细菌和控制有害炎症,有望成为败血症的有效治疗方法。从临床数据分析来看,toll样受体2 (TLR2)和TLR4信号通路是脓毒症发病机制的关键。基于对TLR2/4与其天然配体之间分子相互作用的理解,我们重新设计了一种两亲性、螺旋状、阳离子的肽R18,它能有效抑制TLR2和TLR4的激活,并能根除细菌。这种抑制主要是通过R18与TLR2或TLR4配体和受体结合来实现的,这干扰了配体-受体的相互作用。我们还定义了多肽序列中疏水和阳离子氨基酸残基在这些多作用中的重要作用。通过将R18偶联到自组装的聚乙二醇化磷脂基纳米胶束(命名为M-CR18)上,显著增强了抗菌活性和稳定性。机理研究表明,与分子R18相比,M-CR18通过对细菌膜完整性、生物膜形成和细菌鞭毛组装的三重破坏,有效地消除了细菌。M-CR18在小鼠盲肠结扎穿刺感染性模型和铜绿假单胞菌急性肺损伤模型以及脂多糖(LPS)诱导的非感染性肺炎症模型中验证了其体内疗效。最后,M-CR18能有效消灭临床存在的耐药菌。该研究为具有免疫调节和抗菌活性的多功能纳米器件提供了一种全新的设计原则,它代表了一类用于治疗细菌感染介导的肺炎和败血症的新型纳米抗生素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Designer amphiphilic helical peptide-decorated nanomicelles enable simultaneous inflammation control and triple-destruction of bacteria for treating bacterial pneumonia and sepsis.

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.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
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.
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