Institute of Molecular Sciences and Engineering, Institute of Frontier and Interdisciplinary Science, Shandong University, Qingdao, Shandong, 266237, P. R. China.
Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266035, P. R. China.
Adv Mater. 2024 Feb;36(8):e2308241. doi: 10.1002/adma.202308241. Epub 2023 Dec 8.
Activating the strong immune system is a key initiative to counteract dormant tumors and prevent recurrence. Herein, self-destructive and multienzymatically active copper-quinone-GOx nanoparticles (abbreviated as CQG NPs) have been designed to induce harmonious and balanced pyroptosis and cuproptosis using the "Tai Chi mindset" to awaken the immune response for suppressing dormant and recurrent tumors. This cleverly designed material can disrupt the antioxidant defense mechanism of tumor cells by inhibiting the nuclear factor-erythroid 2-related factor 2 (NRF2)-quinone oxidoreductase 1 (NQO1) signaling pathway. Furthermore, combined with its excellent multienzyme activity, it activates NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis. Meanwhile, cuproptosis can be triggered by copper ions released from the self-destructive disintegration of CQG NPs and the sensitivity of cancer cells to cuproptosis is enhanced through the depletion of endogenous copper chelators via the Michael addition reaction between glutathione (GSH) and quinone ligand, oxygen production from catalase-like reaction, and starvation-induced glucose deficiency. More importantly, CQG NPs-induced pyroptosis and cuproptosis can promote immunosuppressive tumor microenvironment (TME) remodeling, enhance the infiltration of immune cells into the tumor, and activate robust systemic immunity. Collectively, this study provides a new strategy to resist tumor dormancy, prevent tumor recurrence, and improve the clinical prognosis of tumors.
激活强大的免疫系统是对抗休眠肿瘤和预防复发的关键举措。在此,我们设计了具有自毁和多酶活性的铜-醌-GOx 纳米粒子(简称 CQG NPs),采用“太极思维”诱导协调和平衡的细胞焦亡和铜死亡,从而唤醒免疫反应来抑制休眠和复发性肿瘤。这种巧妙设计的材料可以通过抑制核因子-红细胞 2 相关因子 2(NRF2)-醌氧化还原酶 1(NQO1)信号通路来破坏肿瘤细胞的抗氧化防御机制。此外,它还结合其卓越的多酶活性,激活 NOD 样受体蛋白 3(NLRP3)介导的细胞焦亡。同时,CQG NPs 自毁性崩解释放的铜离子以及谷胱甘肽(GSH)与醌配体之间的迈克尔加成反应、过氧化氢酶样反应产生的氧气和饥饿诱导的葡萄糖缺乏导致内源性铜螯合物耗竭,可引发铜死亡。更重要的是,CQG NPs 诱导的细胞焦亡和铜死亡可以促进免疫抑制性肿瘤微环境(TME)重塑,增强免疫细胞浸润肿瘤,并激活强大的全身免疫。总之,本研究为抵抗肿瘤休眠、预防肿瘤复发和改善肿瘤临床预后提供了一种新策略。
Mater Today Bio. 2025-7-29
J Nanobiotechnology. 2025-7-28