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    Simplified α2-macroglobulin as a TNF-α inhibitor for inflammation alleviation in osteoarthritis and myocardial infarction therapy

    Year: 2023

    Authors: Zheng, Weiwei; Zhou, Tong; Zhang, Yuxiang; Ding, Jie; Xie, Jieqi; Wang, Shuqin; Wang, Zhaoyi; Wang, Kai; Shen, Liyin; Zhu, Yang; Gao, Changyou

    Keywords: Inflammation response; Internalization; Tissue injury; Tumor necrosis factor α (TNF-α) inhibitor; α-macroglobulin

    Tumor necrosis factor α (TNF-α) is a leading proinflammatory cytokine as the master regulator of inflammation in chronic inflammation diseases. Although TNF-α antagonists such as small molecules and peptides are in development, comparable effectiveness in TNF-α neutralization is hardly achieved only with TNF-α capture. In this study, simplified α2-macroglobulin (SM) as a novel TNF-α inhibitor was fabricated to relieve inflammation response by TNF-α capture and internalization with lysosomal degradation. SM was prepared by conjugating a TNF-α-targeting peptide with a receptor binding domain (RBD) derived from α2-macroglobulin through a synthetic biology strategy. SM exhibited effective capture and bioactivity inhibition of TNF-α. Improved endocytosis of TNF-α into lysosomes was observed with SM in macrophages. Even challenged with LPS/IFNγ, the macrophages showed relieved inflammation response with SM treatment. When administrated in chronic inflammation injury in vivo, SM achieved comparable therapeutic efficacy with Infliximab, showing ameliorated cartilage degeneration with relieved inflammation in osteoarthritis (OA) and preserved cardiac function with mitigated myocardium injury in myocardial infarction (MI). These results suggest that SM functioning in TNF-α capture-internalization mechanism might be promising therapeutic alternatives of TNF-α antibodies.
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