Ferroptotic cell death results from glutathione peroxidase 4 (GPX4) inactivation and/or glutathione (GSH) depletion. Elevated GSH levels are often found in multidrug‐resistant (MDR) tumor cells, reducing their sensitivity to chemotherapeutic drugs and the efficacy of treatment. MDR cells also acquire a dependency on GPX4, reducing their oxidative stress and promoting their survival. Therefore, the depletion of GSH and inactivation of GPX4 has the potential to be a superior treatment strategy for MDR tumors. Platinum‐decorated gold nanostars (Pt‐AuNS) are presented as a novel metal nanoprodrug for ferroptotic therapy against MDR tumors. Under dark conditions, the synthesized Pt‐AuNS exhibit negligible levels of toxicity. Upon exposure of the Pt‐AuNS to near‐infrared (NIR) light, active metallic (Pt and Au) species are released, subsequently inducing cytotoxicity. The mechanism of action is attributed to GSH depletion and GPX4 inactivation, accumulating lipid hydroperoxides, which in turn leads to ferroptosis. In in vivo xenograft, the MDR cancer model confirmed the NIR light‐activation of Pt‐AuNS prodrugs, resulting in efficient ferroptotic therapeutic action against MDR tumors without long‐term side effects. The findings lay the groundwork for using Pt‐AuNS prodrugs responsive to NIR light as ferroptosis‐inducing agents in chemo‐resistant cancer cells and demonstrate their potential for use in future clinical applications.

中文翻译：

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近红外激活铂装饰的金纳米星，用于协同抗癌药物的光热/金属疗法的协同治疗。

谷胱甘肽过氧化物酶4（GPX4）失活和/或谷胱甘肽（GSH）耗竭导致肥大细胞死亡。经常在多药耐药性（MDR）肿瘤细胞中发现GSH水平升高，从而降低了它们对化疗药物的敏感性和治疗效果。MDR细胞还对GPX4产生依赖性，从而降低其氧化应激并促进其存活。因此，GSH的消耗和GPX4的失活有可能成为MDR肿瘤的优良治疗策略。铂金修饰的金纳米星（Pt-AuNS）作为一种新型金属纳米前体药物，可用于针对MDR肿瘤的促铁疗法。在黑暗条件下，合成的Pt-AuNS的毒性水平可忽略不计。在Pt-AuNS暴露于近红外（NIR）光后，活性金属（Pt和Au）物质被释放，随后诱导细胞毒性。作用机制归因于GSH耗竭和GPX4失活，积累了脂质氢过氧化物，进而导致肥大病。在体内异种移植中，MDR癌症模型证实了Pt-AuNS前药的NIR光激活，从而导致针对MDR肿瘤的有效促铁疗法治疗作用，而没有长期副作用。这些发现为将对NIR光有反应的Pt-AuNS前药用作抗化学性癌细胞中的促肥大病诱导剂奠定了基础，并证明了其在未来临床应用中的潜力。MDR癌症模型证实了Pt-AuNS前药的NIR光活化作用，从而对MDR肿瘤产生了有效的促铁治疗作用，而没有长期的副作用。这些发现为将对NIR光有反应的Pt-AuNS前药用作抗化学性癌细胞中的促肥大病诱导剂奠定了基础，并证明了其在未来临床应用中的潜力。MDR癌症模型证实了Pt-AuNS前药的NIR光活化作用，从而对MDR肿瘤产生了有效的促铁治疗作用，而没有长期的副作用。这些发现为将对NIR光有反应的Pt-AuNS前药用作抗化学性癌细胞中的促肥大病诱导剂奠定了基础，并证明了其在未来临床应用中的潜力。