Cancer cells rely on aerobic glycolysis and DNA repair signals to drive tumor growth and develop drug resistance. Yet, fine-tuning aerobic glycolysis with the assist of nanotechnology, for example, dampening lactate dehydrogenase (LDH) for cancer cell metabolic reprograming remains to be investigated. Here we focus on anaplastic thyroid cancer (ATC) as an extremely malignant cancer with the high expression of LDH, and develop a pH-responsive and nucleus-targeting platinum nanocluster (Pt@TAT/sPEG) to simultaneously targets LDH and exacerbates DNA damage. Pt@TAT/sPEG effectively disrupts LDH activity, reducing lactate production and ATP levels, and meanwhile induces ROS production, DNA damage, and apoptosis in ATC tumor cells. We found Pt@TAT/sPEG also blocks nucleotide excision repair pathway and achieves effective tumor cell killing. In an orthotopic ATC xenograft model, Pt@TAT/sPEG demonstrates superior tumor growth suppression compared to Pt@sPEG and cisplatin. This nanostrategy offers a feasible approach to simultaneously inhibit glycolysis and DNA repair for metabolic reprogramming and enhanced tumor chemotherapy.

中文翻译：

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利用细胞核靶向铂纳米簇破坏未分化甲状腺癌的糖酵解和 DNA 修复


癌细胞依靠有氧糖酵解和 DNA 修复信号来驱动肿瘤生长并产生耐药性。然而，在纳米技术的帮助下微调有氧糖酵解，例如抑制癌细胞代谢重编程的乳酸脱氢酶（LDH）仍有待研究。在这里，我们重点关注未变性甲状腺癌（ATC）这种LDH高表达的恶性癌症，并开发了一种pH响应性和细胞核靶向的铂纳米簇（Pt@TAT/sPEG），以同时靶向LDH并加剧DNA损伤。 Pt@TAT/sPEG 有效破坏 LDH 活性，降低乳酸生成和 ATP 水平，同时诱导 ATC 肿瘤细胞中 ROS 生成、DNA 损伤和凋亡。我们发现Pt@TAT/sPEG还能阻断核苷酸切除修复途径并实现有效的肿瘤细胞杀伤。在原位 ATC 异种移植模型中，与 Pt@sPEG 和顺铂相比，Pt@TAT/sPEG 表现出优异的肿瘤生长抑制作用。这种纳米策略提供了一种同时抑制糖酵解和 DNA 修复以实现代谢重编程和增强肿瘤化疗的可行方法。