基于纳米技术的新型铁死亡驱动疗法要么通过增加细胞内铁水平，要么通过抑制谷胱甘肽过氧化物酶4（GPX4）的活性。然而，同时进行铁输送和GPX4抑制的治疗策略仍然具有挑战性，并且有着很大的改进空间。此外，目前的纳米医学研究主要使用二硫化-巯基交换来耗竭谷胱甘肽（GSH）以实现GPX4的失活，但由于持续的GSH合成的补偿效应，这种方法并不理想。在本研究中，我们设计了一种二合一的诱导铁死亡的纳米平台，利用基于铁的金属-有机框架（MOF）结构来实现铁的输送，并通过加载小分子丁硫必氧胺（BSO）来阻断新生GSH的生物合成，从而实现可持续的GSH消耗和双重铁死亡放大效应。包覆的脂质双层（L）可以增加纳米粒子的稳定性，而修饰的肿瘤靶向肽包含精氨酸-甘氨酸-天冬酰胺（RGD/R）序列能够实现针对肿瘤特异性治疗。此外，降低GSH水平可以缓解肿瘤细胞对化疗药物的抗药性，所以我们还加载了奥沙利铂（OXA）来获得BSO&OXA@MOF-LR，以实现增强的肿瘤化疗-铁死亡联合治疗。BSO&OXA@MOF-LR显示出强大的抑制肿瘤效果，并在4T1肿瘤异种移植小鼠中显著提高了存活率，表明双重增强的铁死亡和GSH消耗使细胞凋亡敏感化。BSO&OXA@MOF-LR被证明是一种有效的铁死亡/凋亡复合抗癌药物。该研究对于基于铁死亡和凋亡的新型抗癌化疗的临床开发具有重要意义。© 2023. BioMed Central Ltd., part of Springer Nature.

Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis.In this study, we design a two-in-one ferroptosis-inducing nanoplatform using iron-based metal-organic framework (MOF) that combines iron supply and GPX4 deactivation by loading the small molecule buthionine sulfoxide amine (BSO) to block de novo GSH biosynthesis, which can achieve sustainable GSH elimination and dual ferroptosis amplification. A coated lipid bilayer (L) can increase the stability of the nanoparticles and a modified tumor-homing peptide comprising arginine-glycine-aspartic acid (RGD/R) can achieve tumor-specific therapies. Moreover, as a decrease in GSH can alleviate resistance of cancer cells to chemotherapy drugs, oxaliplatin (OXA) was also loaded to obtain BSO&OXA@MOF-LR for enhanced cancer chemo-ferrotherapy in vivo.BSO&OXA@MOF-LR shows a robust tumor suppression effect and significantly improved the survival rate in 4T1 tumor xenograft mice, indicating a combined effect of dual amplified ferroptosis and GSH elimination sensitized apoptosis.BSO&OXA@MOF-LR is proven to be an efficient ferroptosis/apoptosis hybrid anti-cancer agent. This study is of great significance for the clinical development of novel drugs based on ferroptosis and apoptosis for enhanced cancer chemo-ferrotherapy.© 2023. BioMed Central Ltd., part of Springer Nature.