An infection-microenvironment-targeted and responsive peptide-drug nanosystem for sepsis emergency by suppressing infection and inflammation

• Published in: Asian journal of pharmceutical sciences Vol. 18; no. 6; pp. 100869 - 143
• Main Authors: He, Wei, Fu, Daan, Gai, Yongkang, Liu, Xingxin, Yang, Chang, Ye, Zhilan, Chen, Xu, Liu, Jia, Chang, Bingcheng
• Format: Journal Article
• Language: English
• Published: Netherlands The Second Clinical College,The Second Affiliated Hospital,Guizhou University of Traditional Chinese Medicine,Guiyang 550003,China%Department of Anesthesiology,Tongji Medical College,Union Hospital,Huazhong University of Science and Technology,Wuhan 430022,China%Department of Nuclear Medicine,Hubei Province Key Laboratory of Molecular Imaging,Tongji Medical College,Union Hospital,Huazhong University of Science and Technology,Wuhan 430022,China%Department of Laboratory Medicine,West China Second University Hospital,Sichuan University,Chengdu 610065,China%Guizhou Provincial Key Laboratory of Pharmaceutics,Guizhou Medical University,Guiyang 550004,China%Department of Geriatrics,Tongji Medical College,Union Hospital,Huazhong University of Science and Technology,Wuhan 430022,China%Research Center for Tissue Engineering and Regenerative Medicine,Tongji Medical College,Union Hospital,Huazhong University of Science and Technology,Wuhan 430022,China 01.11.2023; Elsevier
• Subjects: Infectious microenvironments; Nanoscale drug delivery systems; Omiganan; Pathogens; Sepsis; Infectious microenvironments; Pathogens; Sepsis; Nanoscale drug delivery systems; Omiganan
• ISSN: 1818-0876; 2221-285X; 2221-285X
• DOI: 10.1016/j.ajps.2023.100869

Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation. Nevertheless, current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens. Omiganan, an antimicrobial peptide, has shown promise for neutralizing endotoxins and eliminating diverse pathogens. However, its clinical application is hindered by safety and stability concerns. Herein, we present a nanoscale drug delivery system (Omi-hyd-Dex@HA NPs) that selectively targets infectious microenvironments (IMEs) and responds to specific stimuli for efficient intervention in sepsis. The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid (HA). The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes, but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase. The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation. In multiple tissue infection and sepsis animal models, Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction, thereby preventing subsequent fatal complications and significantly improving survival outcomes. The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.