Ferroptosis and autophagy, playing significant roles in tumor treatment, are two typical forms of the programmed cell death. However, the rational combination of ferroptosis and autophagy for synergistic tumor therapy is still highly challenging. Herein, we report on an intriguing nanomedicine strategy for achieving autophagy-enhanced ferroptosis on efficiently combating cancer, which was based on the construction of trehalose-loaded mSiO₂@MnO_x-mPEG (TreMMM) nanoparticles with satisfactory biocompatibility. The nanoparticles are endowed with high glutathione (GSH) consumption efficiency, thereby inducing cancer-cell ferroptosis via inactivating glutathione peroxidases 4 (GPX4). Subsequently, the TreMMM degradation due to the GSH depletion and pH sensitivity contributed to the trehalose release for inducing autophagy, promoting/enhancing ferroptosis by NCOA4-mediated degradation of ferritin. A substantial in vitro and in vivo antitumor effect was achieved by such an intriguing autophagy-enhanced ferroptosis. Therefore, the rational combination of GSH-consumption-induced ferroptosis and trehalose-induced autophagy by nanomedicine design provides an alternative but effective strategy for tumor treatment.

铁死亡和自噬在肿瘤治疗中起着重要作用，是程序性细胞死亡的两种典型形式。然而，将铁死亡和自噬合理结合用于协同肿瘤治疗仍然具有很大的挑战性。在此，我们报告了一种有趣的纳米医学策略，用于实现自噬增强的铁死亡以有效抗癌，该策略基于海藻糖负载的 mSiO ₂ @MnO _x的构建-mPEG (TreMMM) 纳米粒子具有令人满意的生物相容性。纳米颗粒具有高谷胱甘肽 (GSH) 消耗效率，从而通过灭活谷胱甘肽过氧化物酶 4 (GPX4) 诱导癌细胞铁死亡。随后，由于 GSH 耗尽和 pH 敏感性导致的 TreMMM 降解有助于海藻糖释放以诱导自噬，通过 NCOA4 介导的铁蛋白降解促进/增强铁死亡。这种有趣的自噬增强铁死亡实现了显着的体外和体内抗肿瘤作用。因此，通过纳米药物设计将 GSH 消耗诱导的铁死亡和海藻糖诱导的自噬合理结合，为肿瘤治疗提供了一种替代但有效的策略。