用于精确蛋白质降解和协同免疫治疗的蛋白质水解靶向嵌合体的逻辑门控生物正交原位合成
Logic-Gated Bioorthogonal In Situ Synthesis of Proteolysis-Targeting Chimeras for Precise Protein Degradation and Synergistic Immunotherapy.
摘要(中文译文)
以传统小分子抑制剂或常规蛋白水解靶向嵌合体（PROTAC）靶向谷胱甘肽过氧化物酶4（GPX4）受到不可控全身毒性的限制。为克服这一局限，我们设计了一种纳米系统（GV@Ce6-Cu，GVCC），其核心是在肿瘤微环境（TME）特异性“与”逻辑门的严格调控下，通过生物正交原位合成PROTAC，该逻辑门同时对过表达的组织蛋白酶B（CTSB）和升高的谷胱甘肽（GSH）作出响应。在肿瘤微环境中，CTSB特异性切割肽前体使其成为功能性片段，同时GSH将共递送的Cu还原为活性Cu催化剂。只有两种输入同时作用，才能实现片段的原位生物正交连接，形成具有活性的GPX4降解型PROTAC。这种精准合成 orchestrated 了一系列功能级联。原位生成的PROTAC通过降解GPX4启动铁死亡；该效应被共释放的铜离子（驱动铜死亡）和氯e6（Ce6）介导的光动力治疗（PDT）强力放大，共同产生大量活性氧爆发。这种铁死亡与铜死亡的协同诱导，在PDT的增强下，触发强烈的免疫原性细胞死亡。因此，GVCC治疗重编程了免疫抑制性三阴性乳腺癌微环境，并与抗PD-L1免疫检查点阻断表现出强效协同作用。本研究确立了生物正交原位PROTAC合成作为一种有效的癌症精准治疗策略。
Abstract
Targeting glutathione peroxidase 4 (GPX4) with traditional small-molecule inhibitors or conventional proteolysis-targeting chimeras (PROTACs) is limited by uncontrollable systemic toxicity. To overcome this, we engineered a nanosystem (GV@Ce6-Cu, GVCC) centered on the bioorthogonal in situ synthesis of a PROTAC, strictly governed by a tumor microenvironment (TME)-specific "AND" logic gate responsive to both overexpressed cathepsin B (CTSB) and elevated glutathione (GSH). Within the TME, CTSB specifically cleaves a peptide precursor into functional fragments, while GSH simultaneously reduces a codelivered Cu to the active Cu catalyst. Only the concurrent action of both inputs enables the bioorthogonal ligation of the fragments in situ to form the active GPX4-degrading PROTAC. This precise synthesis orchestrates a cascade of functions. The in situ-generated PROTAC initiates ferroptosis by degrading GPX4; this effect is powerfully amplified by coreleased copper ions (driving cuproptosis) and by chlorin e6 (Ce6)-mediated photodynamic therapy (PDT), which together generate a massive reactive oxygen species burst. This cooperative induction of ferroptosis and cuproptosis, augmented by PDT, triggers robust immunogenic cell death. Consequently, GVCC treatment reprograms the immunosuppressive triple-negative breast cancer microenvironment and demonstrates potent synergy with anti-PD-L1 checkpoint blockade. This study establishes bioorthogonal in situ PROTAC synthesis as an effective precision strategy for cancer therapy.
如何引用
AMA
Jiasha Wu, Luyi Wang, Shiqin Jian, Rui Ji, Yan Zuo, Siyao Liu, et al. Logic-Gated Bioorthogonal In Situ Synthesis of Proteolysis-Targeting Chimeras for Precise Protein Degradation and Synergistic Immunotherapy.. ACS nano. 2026; doi:10.1021/acsnano.6c04279.
APA
Jiasha Wu, Luyi Wang, Shiqin Jian, Rui Ji, Yan Zuo, Siyao Liu, et al (2026). Logic-Gated Bioorthogonal In Situ Synthesis of Proteolysis-Targeting Chimeras for Precise Protein Degradation and Synergistic Immunotherapy.. ACS nano. https://doi.org/10.1021/acsnano.6c04279
GB/T 7714
Jiasha Wu, Luyi Wang, Shiqin Jian, Rui Ji, Yan Zuo, Siyao Liu, et al. Logic-Gated Bioorthogonal In Situ Synthesis of Proteolysis-Targeting Chimeras for Precise Protein Degradation and Synergistic Immunotherapy.[J]. ACS nano, 2026 doi:10.1021/acsnano.6c04279.
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