{
    "abstract": "Targeted protein degradation (TPD) technology holds significant potential for modulating protein homeostasis and treating diseases. However, current methods for degrading membrane protein highly depend on the lysosome-targeting ligands or membrane receptors. In this study, we present a set of multivalent targeting chimeras (multi-TACs) for tumor-specific degradation of programmed death ligand 1 (PD-L1) on the surface of tumor cell membrane. The multi-TACs are synthesized by copolymerization of small molecule PD-L1 inhibitor BMS-1 with acid-responsive monomers. The chemical structures of the multi-TACs are optimized by investigating the correlation between PD-L1 degradation efficacy and the key parameters including acid-sensitive moieties, BMS-1 valences and spacer lengths. Mechanistic study reveals that the multi-TACs highly efficiently degrade PD-L1 on the surface of tumor cells via the adsorption-mediated endocytosis and lysosomal degradation pathways, which differ significantly from the reported strategies for membrane protein degradation. The outperformed multi-TAC GG56 with tumor extracellular acidity and enzyme-sensitivity dramatically reduces PD-L1 levels and suppresses tumor growth in mouse models of B16-F10 melanoma and 4T1 breast tumors. Furthermore, GG56 serves as a versatile nanoplatform for combinatory chemo-immunotherapy and radio-immunotherapy of 4T1 breast tumor by co-delivery of chemotherapeutic and radio-sensitizer, respectively.",
    "authors": [
        {
            "affiliation": "East China Normal University, School of Chemistry and Moleculor Engineering, CHINA.",
            "firstname": "Huiling",
            "initials": "H",
            "lastname": "Zhou"
        },
        {
            "affiliation": "Shanghai Institute of Materia Medica CAS: Shanghai Institute of Materia Medica Chinese Academy of Sciences, State Key Laboratory of Chemical Biology and Center of Pharmaceutics, CHINA.",
            "firstname": "Bo",
            "initials": "B",
            "lastname": "Hou"
        },
        {
            "affiliation": "Shanghai Institute of Materia Medica CAS: Shanghai Institute of Materia Medica Chinese Academy of Sciences, State Key Laboratory of Chemical Biology and Center of Pharmaceutics, CHINA.",
            "firstname": "Yiming",
            "initials": "Y",
            "lastname": "Shan"
        },
        {
            "affiliation": "Shanghai Institute of Materia Medica CAS: Shanghai Institute of Materia Medica Chinese Academy of Sciences, State Key Laboratory of Chemical Biology and Center of Pharmaceutics, CHINA.",
            "firstname": "Lujia",
            "initials": "L",
            "lastname": "Huang"
        },
        {
            "affiliation": "Shanghai Institute of Materia Medica CAS: Shanghai Institute of Materia Medica Chinese Academy of Sciences, State Key Laboratory of Chemical Biology and Center of Pharmaceutics, CHINA.",
            "firstname": "Fangmin",
            "initials": "F",
            "lastname": "Chen"
        },
        {
            "affiliation": "Shanghai Institute of Materia Medica CAS: Shanghai Institute of Materia Medica Chinese Academy of Sciences, State Key Laboratory of Chemical Biology and Center of Pharmaceutics, CHINA.",
            "firstname": "Siyuan",
            "initials": "S",
            "lastname": "Ren"
        },
        {
            "affiliation": "East China Normal University, School of Chemistry and Molecular Engineering, CHINA.",
            "firstname": "Shunan",
            "initials": "S",
            "lastname": "Zhang"
        },
        {
            "affiliation": "Shanghai Institute of Materia Medica CAS: Shanghai Institute of Materia Medica Chinese Academy of Sciences, State Key Laboratory of Chemical Biology and Center of Pharmaceutics, CHINA.",
            "firstname": "Jiaxing",
            "initials": "J",
            "lastname": "Pan"
        },
        {
            "affiliation": "East China Normal University, School of Chemistry and Moleculor Engineering, CHINA.",
            "firstname": "Yijing",
            "initials": "Y",
            "lastname": "Dang"
        },
        {
            "affiliation": "Shanghai Institute of Materia Medica CAS: Shanghai Institute of Materia Medica Chinese Academy of Sciences, State Key Laboratory of Chemical Biology and Center of Pharmaceutics, CHINA.",
            "firstname": "Haijun",
            "initials": "H",
            "lastname": "Yu"
        },
        {
            "affiliation": "East China Normal University, School of Chemistry and Moleculor Engineering, No. 500 Dongchuan Road, 200241, Shanghai, CHINA.",
            "firstname": "Zhiai",
            "initials": "Z",
            "lastname": "Xu"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 2025 Wiley\u2010VCH GmbH.",
    "doi": "10.1002/anie.202504233",
    "journal": "Angewandte Chemie (International ed. in English)",
    "keywords": [
        "Combinatory therapy",
        "Immune Checkpoint Blockade",
        "Multivalent targeting chimeras",
        "Tumor microenvironment",
        "Tumor-specific PD-L1 degradation"
    ],
    "methods": null,
    "publication_date": "2025-04-26",
    "pubmed_id": "40285333",
    "results": null,
    "title": "De-novo Design of Structure-tunable Multivalent Chimeras for Tumor-Targeted PD-L1 Degradation and Potentiated Cancer Immunotherapy.",
    "xml": "<Element 'PubmedArticle' at 0x788506a0e980>"
}