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    Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy

    Year: 2023

    Authors: Shin, Sol; Ko, Hyewon; Kim, Chan Ho; Yoon, Bo Kyeong; Son, Soyoung; Lee, Jae Ah; Shin, Jung Min; Lee, Jeongjin; Song, Seok Ho; Jackman, Joshua A.; Park, Jae Hyung

    Keywords: Biological physics; Cancer immunotherapy; Nanobiotechnology

    Tumour-derived exosomes (T-EXOs) impede immune checkpoint blockade therapies, motivating pharmacological efforts to inhibit them. Inspired by how antiviral curvature-sensing peptides disrupt membrane-enveloped virus particles in the exosome size range, we devised a broadly useful strategy that repurposes an engineered antiviral peptide to disrupt membrane-enveloped T-EXOs for synergistic cancer immunotherapy. The membrane-targeting peptide inhibits T-EXOs from various cancer types and exhibits pH-enhanced membrane disruption relevant to the tumour microenvironment. The combination of T-EXO-disrupting peptide and programmed cell death protein-1 antibody-based immune checkpoint blockade therapy improves treatment outcomes in tumour-bearing mice. Peptide-mediated disruption of T-EXOs not only reduces levels of circulating exosomal programmed death-ligand 1, but also restores CD8+ T cell effector function, prevents premetastatic niche formation and reshapes the tumour microenvironment in vivo. Our findings demonstrate that peptide-induced T-EXO depletion can enhance cancer immunotherapy and support the potential of peptide engineering for exosome-targeting applications.
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