Ferroptosis, a newfound non-apoptotic cell death pathway, results from the accumulation of iron-dependent lipid peroxide (LPO). Recently, emerging iron-based nanomaterials have been extensively developed to induce Fenton reaction-dependent ferroptosis for cancer therapy. However, insufficient amount of H₂O₂ and limited acidity of tumor could not satisfy the optimal conditions for Fenton reaction, which extremely limited the efficacy of ferroptosis therapy. Herein, we report a novel glutathione (GSH) and iron redox couple sequentially triggered LPO generator (LPOgener) which can directly supply the Fenton reaction-independent downstream executioner of ferroptosis for cancer therapy. By harnessing GSH-mediated Fe³⁺ reduction and the well-established iron redox couple-mediated lipid peroxidation, LPOgener was constructed by complete ferric ammonium citrate (FAC) and unsaturated lipids-rich phosphatidylcholine, and formed as FAC loaded liposome. The Fe³⁺ encapsulated in LPOgener could be efficiently reduced to Fe²⁺ under high GSH level in tumor cells. Subsequently, the formed iron redox couple could trigger overwhelming lipid peroxidation for Fenton reaction-independent ferroptosis. Superior anticancer therapeutic effect with little systemic toxicity demonstrated that LPOgener was a potent ferroptosis-inducing agent for cancer therapy. Therefore, to directly supply the druglike, easily prepared, GSH and iron redox couple sequentially triggered LPOgener would provide a new direction in designing strategies for ferroptosis therapy.

Ferroptosis是一种新发现的非凋亡性细胞死亡途径，由铁依赖性脂质过氧化物（LPO）的积累引起。近来，已广泛开发了新兴的铁基纳米材料以诱导Fenton反应依赖性肥大症用于癌症治疗。然而，H ₂ O _2的量不足和肿瘤的酸度不能满足Fenton反应的最佳条件，这极大地限制了肥大症治疗的疗效。在本文中，我们报道了一种新型谷胱甘肽（GSH）和铁氧化还原对顺序触发的LPO生成器（LPOgener），该生成器可以直接提供不依赖Fenton反应的肥大症的下游执行者用于癌症治疗。利用GSH介导的Fe ³⁺通过完整的柠檬酸铁铵（FAC）和富含不饱和脂质的磷脂酰胆碱构建LPOgener，并还原为已建立的FAC脂质体。LPOgener中封装的Fe ³⁺可以有效地还原为Fe ²⁺在肿瘤细胞中高谷胱甘肽水平下 随后，形成的铁氧化还原对可能引发不依赖Fenton反应的肥大病的压倒性脂质过氧化作用。优异的抗癌治疗效果，几乎没有全身毒性，这表明LPOgener是一种有效的促发肥大病诱导剂。因此，为直接提供易于制备的药物样药物，GSH和铁氧化还原对依次触发LPOgener会为铁素体病治疗策略的设计提供新的方向。