Cun Ju-E, He Ziyun, Fan Xi, Pan Qingqing, Luo Kui, He Bin, Pu Yuji
National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Med-X Center for Materials, Sichuan University, Chengdu, 610064, China.
School of Preclinical Medicine, Chengdu University, Chengdu, 610106, China.
Small. 2025 Feb;21(6):e2409875. doi: 10.1002/smll.202409875. Epub 2025 Jan 5.
Copper-based nanoparticles have garnered significant interest in cancer therapy due to their ability to induce oxidative stress and cuproptosis in cancer cells. However, their antitumor effectiveness is constrained by the dynamic redox balance and the metabolic shift between oxidative phosphorylation and glycolysis. Here, a polydopamine-coated copper-α-ketoglutaric acid (α-KG) coordination polymer nanoparticle (CKPP) is designed for combined pyroptosis-cuproptosis cancer immunotherapy by amplifying reactive oxygen species (ROS) production and regulating cellular metabolism. The intracellular redox imbalance is achieved through the synergistic effects of α-KG-induced mitochondrial metabolic reprogramming, photothermally enhanced superoxide dismutase-like activity of polydopamine, and glutathione depletion by copper ions. The multifaceted redox modulation results in a substantial increase in intracellular ROS levels, triggering oxidative stress and subsequent pyroptosis in cancer cells. Furthermore, α-KG shifts cellular metabolism from glycolysis to oxidative phosphorylation, thereby enhancing cuproptosis induced by copper ions. The combination of ROS dyshomeostasis and glycolysis inhibition results in a potent enhancement of pyroptosis-cuproptosis-mediated cancer therapy. In a murine model of colorectal cancer, CKPP exhibited a remarkable anticancer effect, achieving a tumor inhibition rate of 96.3% and complete tumor eradication in two out of five cases. Overall, this bio-engineered metal-organic nanocomposite demonstrates significant potential for treating cancer through combined pyroptosis-cuproptosis cancer immunotherapy.
铜基纳米颗粒因其能够在癌细胞中诱导氧化应激和铜死亡而在癌症治疗中引起了广泛关注。然而，它们的抗肿瘤效果受到动态氧化还原平衡以及氧化磷酸化和糖酵解之间代谢转变的限制。在此，设计了一种聚多巴胺包覆的铜-α-酮戊二酸（α-KG）配位聚合物纳米颗粒（CKPP），通过放大活性氧（ROS）生成和调节细胞代谢来进行联合焦亡-铜死亡癌症免疫治疗。通过α-KG诱导的线粒体代谢重编程、聚多巴胺光热增强的超氧化物歧化酶样活性以及铜离子导致的谷胱甘肽耗竭的协同作用，实现了细胞内氧化还原失衡。多方面的氧化还原调节导致细胞内ROS水平大幅增加，引发癌细胞中的氧化应激和随后的焦亡。此外，α-KG将细胞代谢从糖酵解转变为氧化磷酸化，从而增强铜离子诱导的铜死亡。ROS稳态失衡和糖酵解抑制的结合导致焦亡-铜死亡介导的癌症治疗效果显著增强。在小鼠结直肠癌模型中，CKPP表现出显著的抗癌效果，实现了96.3%的肿瘤抑制率，并且在五例中有两例实现了肿瘤完全消除。总体而言，这种生物工程金属有机纳米复合材料通过联合焦亡-铜死亡癌症免疫治疗在治疗癌症方面显示出巨大潜力。
