Rui Niu, Bin Zhang, Yang Liu, Bo Xu, Ruiping Deng, Shuyan Song, Kai Liu, Yinghui Wang, Hongjie Zhang
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引用次数: 0
摘要
焦亡可引起肿瘤细胞强烈的免疫原性死亡(ICD),用于抗肿瘤免疫治疗。而富马酸在肿瘤微环境(tumor microenvironment, TME)中的代谢紊乱可显著降低焦亡率,使T淋巴细胞功能失调。本研究利用超声(US)驱动的压电电荷辅助铁基SAzyme (BFTM),共负载三苯基磷(TPP)和甲基(Z)-4-(氯(2-苯基腙)甲基)苯甲酸甲酯(MMB,一种富马酸盐的生物正交试剂),用于激活焦亡和调节富马酸盐的代谢。钛酸钡(BTO)产生的正电荷和负电荷调节了单铁原子的电子云密度,使BFTM具有高效的活性氧(ROS)产生能力,从而触发caspase-1相关的gasdermin D (GSDMD)介导的焦亡。同时,通过生物正交反应消耗细胞内富马酸,不仅可以阻止GSDMD中半胱氨酸的琥珀酸,使其被caspase-1激活和寡聚,从而增强焦亡,还可以恢复ZAP70的磷酸化,使T细胞受体(TCR)信号通路正常化,使CD8+ T细胞恢复活力。简而言之,美国驱动的BFTM作为焦亡引发剂和代谢免疫激活剂,通过ROS风暴、富马酸消耗、触发焦亡和激活T淋巴细胞,显著增强抗肿瘤免疫治疗效果。
Spatiotemporal Charging Single-Atom Nanozymes Activated Pyroptosis for Antitumor Immunotherapy via Bioorthogonal Disruption of Succination and Reinvigorating T Lymphocytes
Pyroptosis can trigger strong immunogenic cell death (ICD) of tumor cells for antitumor immunotherapy. However, metabolic disorders of fumarate in the tumor microenvironment (TME) can significantly reduce the pyroptosis rate and render T lymphocytes dysfunctional. Here, the ultrasound (US)-driven piezoelectric charges assisted Fe-based SAzyme (BFTM) with co-loaded triphenylphosphonium (TPP) and methyl (Z)-4-(chloro(2-phenylhydrazono)methyl)benzoate (MMB, a bioorthogonal reagent of fumarate) for activating pyroptosis and regulating fumarate metabolism is developed. Positive and negative charges generated by barium titanate (BTO) regulate the electron cloud density of single-Fe atom, endowing the BFTM with efficient reactive oxygen species (ROS) production ability for triggering caspase-1 related gasdermin D (GSDMD) mediated pyroptosis. Meanwhile, the consumption of intracellular fumarate through bioorthogonal reaction not only prevented the succinate of cysteines in GSDMD, causing it to be activated and oligomerized by caspase-1 to enhance pyroptosis but also restored the phosphorylation of ZAP70 to normalize the T cell receptor (TCR) signaling pathways for reinvigorating CD8+ T cells. In short, US-driven BFTM as a pyroptosis initiator and metabolism immune activator significantly enhances antitumor immunotherapy effects via ROS storms, fumarate depletion, triggering pyroptosis, and reinvigorating T lymphocytes.
期刊介绍:
Advanced Materials, one of the world's most prestigious journals and the foundation of the Advanced portfolio, is the home of choice for best-in-class materials science for more than 30 years. Following this fast-growing and interdisciplinary field, we are considering and publishing the most important discoveries on any and all materials from materials scientists, chemists, physicists, engineers as well as health and life scientists and bringing you the latest results and trends in modern materials-related research every week.