铁死亡（Ferroptosis）的特征是铁积累和脂质过氧化。然而，临床剂量的Fe3O4纳米颗粒不能有效引起肿瘤中的铁死亡，其机制尚未完全理解。在本研究中，我们利用RNA-seq数据发现，肿瘤细胞可以通过上调Nrf-2表达来反馈激活抗氧化系统，从而避免由Fe3O4纳米颗粒引起的铁死亡。我们还发现，当DHJS（一种用于ROS产生的探针）与Fe3O4纳米颗粒协同作用时，可以拮抗Nrf-2的表达，从而在肿瘤细胞中诱导铁死亡。基于这些发现，我们创建了一种PLGA载荷的Fe3O4和DHJS伪装的仿生混合细胞膜，用于治疗骨肉瘤。这种混合细胞膜赋予了核心纳米颗粒延长的血液循环寿命和增强的同源靶向能力。此外，纳米颗粒中的DHJS和Fe3O4能够协同诱导肿瘤细胞的致命铁死亡，同时在肿瘤中诱导巨噬细胞M1极化以及CD8(+)T细胞和树突状细胞的浸润。总之，本研究为Fe3O4纳米颗粒引发铁死亡提供了新的机制洞察和实用策略。与此同时，合成的仿生纳米颗粒对骨肉瘤展示了协同的铁死亡/免疫治疗效应。

Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of Fe3O4 nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by Fe3O4 nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with Fe3O4 nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded Fe3O4 and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and Fe3O4 in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of Fe3O4 nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.