铁死亡已成为一种有效的非凋亡细胞死亡形式，它为避免凋亡途径的化学耐药性提供了一种有前途的替代方案，并成为癌症的脆弱性。在此，我们构建了一种仿生自组装纳米前药系统，能够共同递送吉非替尼（Gefi）、二茂铁（Fc）和二氢青蒿素（DHA），用于铁死亡和细胞凋亡的联合治疗。在肿瘤微环境中，这种纳米前药能够在高水平的 GSH 下分解并触发药物释放。有趣的是，释放的DHA可以下调GPX4水平，从而增强Fc的细胞内铁死亡，在Gefi的伴随化疗下进一步执行肿瘤细胞死亡。更重要的是，这种纳米前药通过包被相关细胞膜提供高度同源的靶向能力，对肿瘤生长和转移具有出色的抑制作用，并且在治疗过程中没有明显的副作用。这种简单的小分子自组装纳米前药为铁死亡联合化疗提供了一种新的合理设计的模式。© 2023 沉阳药科大学。由 Elsevier B.V. 出版

Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer. Herein, we have constructed a biomimetic self-assembly nano-prodrug system that enables the co-delivery of gefitinib (Gefi), ferrocene (Fc) and dihydroartemisinin (DHA) for the combined therapy of both ferroptosis and apoptosis. In the tumor microenvironment, this nano-prodrug is able to disassemble and trigger drug release under high levels of GSH. Interestingly, the released DHA can downregulate GPX4 level for the enhancement of intracellular ferroptosis from Fc, further executing tumor cell death with concomitant chemotherapy by Gefi. More importantly, this nano-prodrug provides highly homologous targeting ability by coating related cell membranes and exhibits outstanding inhibition of tumor growth and metastasis, as well as no noticeable side-effects during treatments. This simple small molecular self-assembled nano-prodrug provides a new reasonably designed modality for ferroptosis-combined chemotherapy.© 2023 Shenyang Pharmaceutical University. Published by Elsevier B.V.