肺癌化疗药物通常会引起细胞凋亡抵抗，导致治疗结果不佳。 FIN56 可以成为肺癌的潜在治疗方法，因为它能诱导非凋亡性细胞死亡，即铁死亡。然而，FIN56诱导的铁死亡治疗存在瓶颈；具体来说，FIN56无法诱导足够的氧化应激，甚至可能触发铁死亡的防御系统，导致治疗效果不佳。为了克服这一问题，本研究提出了联合递送FIN56和胡椒长明的策略，通过增加氧化应激和连接自噬途径来增强铁死亡的治疗效果。 FIN56 和 Piperlongumine 被封装到基于丝素蛋白的纳米干扰物中，命名为 FP@SFN。表征结果表明，FP@SFN的粒径在纳米范围内且分布均匀。体内和体外研究均表明FP@SFN可以有效消除A549细胞并抑制皮下肺癌肿瘤。值得注意的是，铁死亡和自噬被认为是主要的细胞死亡途径，纳米干扰物通过它们增加氧化应激并促进细胞膜破裂。总之，纳米干扰物可以通过铁死亡-自噬协同机制有效增强铁死亡治疗肺癌的治疗效果，为相关疗法的开发提供参考。版权所有©2024。出版者：Elsevier B.V.

Chemotherapy agents for lung cancer often cause apoptotic resistance in cells, leading to suboptimal therapeutic outcomes. FIN56 can be a potential treatment for lung cancer as it induces non-apoptotic cell death, namely ferroptosis. However, a bottleneck exists in FIN56-induced ferroptosis treatment; specifically, FIN56 fails to induce sufficient oxidative stress and may even trigger the defense system against ferroptosis, resulting in poor therapeutic efficacy. To overcome this, this study proposed a strategy of co-delivering FIN56 and piperlongumine to enhance the ferroptosis treatment effect by increasing oxidative stress and connecting with the autophagy pathway. FIN56 and piperlongumine were encapsulated into silk fibroin-based nano-disruptors, named FP@SFN. Characterization results showed that the particle size of FP@SFN was in the nanometer range and the distribution was uniform. Both in vivo and in vitro studies demonstrated that FP@SFN could effectively eliminate A549 cells and inhibit subcutaneous lung cancer tumors. Notably, ferroptosis and autophagy were identified as the main cell death pathways through which the nano-disruptors increased oxidative stress and facilitated cell membrane rupture. In conclusion, nano-disruptors can effectively enhance the therapeutic effect of ferroptosis treatment for lung cancer through the ferroptosis-autophagy synergy mechanism, providing a reference for the development of related therapeutics.Copyright © 2024. Published by Elsevier B.V.