Ferroptosis can induce cell death that leverages Fe²⁺-triggered Fenton reactions within living organisms, leading to an excessive accumulation of lipid peroxides (LPOs) and inducing cell death. Ferroptosis can effectively circumvent the inevitable drug resistance encountered with traditional apoptotic therapies. However, several issues remain in the clinical application of ferroptosis anticancer therapy, primarily due to the poor efficiency of intracellular Fenton reaction. To address this issue, we developed a supramolecular self-assembled codelivery nanoprodrug (DOX@C18Fc-Q[7] NPs) composed of ferrocene (Fc)-based supramolecular amphiphiles (C18Fc-Q[7]) and a nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). The C18Fc-Q[7] is based on Fc linked to a hydrophobic long-chain alkane via a disulfide linkage, which interacts with hydrophilic Q[7] to form self-assembled amphiphiles. Importantly, the host–guest interaction between Q[7] and Fc effectively enhances the solubility of Fc while maintaining the stability of the Fe²⁺ source. Moreover, C18Fc-Q[7] also acts as a good carrier for loading DOX due to its good self-assembly. In cancer cells, elevated glutathione (GSH) triggers the disassembly of nanoprodrug, leading to the release of DOX, which upregulates NOX4 expression and increases H₂O₂ level, thereby promoting an efficient Fenton reaction for Fc-induced ferroptosis. Moreover, DOX induces cell death through apoptosis, providing a synergistic effect to further enhance the ferroptosis therapy. In vivo studies have demonstrated that this enhanced ferroptosis therapy effectively inhibits tumor growth and metastasis while maintaining good biosafety.

中文翻译：

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一种用于增强铁死亡治疗的超分子自组装纳米前药


铁死亡可诱导细胞死亡，利用生物体内 Fe²⁺ 触发的 Fenton 反应，导致脂质过氧化物 （LPO） 过度积累并诱导细胞死亡。铁死亡可以有效规避传统凋亡疗法不可避免的耐药性。然而，铁死亡抗癌治疗的临床应用仍然存在一些问题，主要是由于细胞内 Fenton 反应的效率差。为了解决这个问题，我们开发了一种超分子自组装共递送纳米前药 （DOX@C18Fc-Q[7] NPs），由基于二茂铁 （Fc） 的超分子两亲物 （C18Fc-Q[7]） 和烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4 （NOX4） 激活剂 （doxorubicin， DOX） 组成。C18Fc-Q[7] 基于通过二硫键与疏水性长链烷烃连接的 Fc，二硫键与亲水性 Q[7] 相互作用形成自组装的两亲物。重要的是，Q[7] 和 Fc 之间的主客体相互作用有效地增强了 Fc 的溶解度，同时保持了 Fe²⁺ 源的稳定性。此外，C18Fc-Q[7] 由于其良好的自组装性，还可以作为加载 DOX 的良好载体。在癌细胞中，谷胱甘肽 （GSH） 升高触发纳米前药的分解，导致 DOX 的释放，DOX 上调 NOX4 表达并增加 H₂O₂ 水平，从而促进 Fc 诱导的铁死亡的有效 Fenton 反应。此外，DOX 通过细胞凋亡诱导细胞死亡，提供协同效应以进一步增强铁死亡治疗。体内研究表明，这种增强的铁死亡疗法可有效抑制肿瘤生长和转移，同时保持良好的生物安全性。