肿瘤代谢重编程需要高水平的三磷酸腺苷（ATP）来维持治疗抵抗，这对化疗和光热疗法提出了重大挑战。特别是，高水平的ATP促进铜离子外流，从而限制铜凋亡的疗效。在这里，合成了一种 H2S 响应介孔 Cu2Cl(OH)3 负载化疗顺铂 (CDDP)，并通过静电作用与碳点 (CDs) 封装最终纳米颗粒 CDDP@Cu2Cl(OH)3-CDs (CDCuCDs) ）。 CDCuCDs 与结肠肿瘤中过量产生的 H2S 反应，产生用于光热治疗的光热硫化铜。通过裂解释放CDDP以达到化疗效果。重要的是，CDDP通过级联反应提高细胞内的H2O2水平，并通过H2O2和Cu之间的化学动力学治疗不断将H2O2转化为高细胞毒性·OH，从而使纳米颗粒产生·OH并提高化疗效果。剧毒•OH 会破坏线粒体稳态，阻止其执行正常的供能功能。下调的ATP抑制热休克蛋白表达，促进温和光热疗法的治疗效果，减少细胞内铜离子的外流，从而提高铜凋亡的治疗效果。我们的研究提供了一种潜在的治疗策略，利用肿瘤中过量产生的 H2S 反应，使肿瘤微环境激活的·OH 纳米发电机能够促进肿瘤能量重塑以进行癌症治疗。版权所有 © 2024。由 Elsevier B.V 出版。

Tumor metabolic reprogramming requires high levels of adenosine triphosphate (ATP) to maintain treatment resistance, which poses major challenges to chemotherapy and photothermal therapy. Especially, high levels of ATP promote copper ion efflux for limiting the curative effect of cuproptosis. Here, an H2S-responsive mesoporous Cu2Cl(OH)3-loading chemotherapeutic cisplatin (CDDP) was synthesized, and the final nanoparticle, CDDP@Cu2Cl(OH)3-CDs (CDCuCDs), was encapsulated by electrostatic action with carbon dots (CDs). CDCuCDs reacted with overproduction H2S in colon tumor to produce photothermic copper sulfide for photothermal therapy. CDDP was released by lysis to achieve chemotherapeutic effects. Importantly, CDDP elevated H2O2 levels in cells through a cascade reaction and continuously transforms H2O2 into highly cytotoxic •OH through chemodynamic therapy between H2O2 and Cu+, which enables nanoparticles to generate •OH and improve the chemotherapeutic efficacy. Highly toxic •OH disrupts mitochondrial homeostasis, prohibiting it from performing normal energy-supplying functions. Down-regulated ATP inhibits heat shock protein expression, which promotes the therapeutic effect of mild photothermal therapy and reduces the efflux of intracellular copper ions, thus improving the therapeutic effect of cuproptosis. Our research provides a potential therapeutic strategy using overproduction H2S responses in tumors, allowing tumor microenvironment-activated •OH nanogenerators to promote tumor energy remodeling for cancer treatment.Copyright © 2024. Published by Elsevier B.V.