Ferroptosis, an iron-dependent regulated cell death process driven by excessive lipid peroxides, can enhance cancer vulnerability to chemotherapy, targeted therapy and immunotherapy. As an essential upstream process for ferroptosis activation, lipid peroxidation of biological membranes is expected to be primarily induced by intrabilayer reactive oxygen species (ROS), indicating a promising strategy to initiate peroxidation by improving the local content of diffusion-limited ROS in the lipid bilayer. Herein, liposomes embedded with PEG-coated 3 nm γ-Fe2O3 nanoparticles in the bilayer (abbreviated as Lp-IO) were constructed to promote the intrabilayer generation of hydroxyl radicals (•OH) from hydrogen peroxide (H2O2), and the integration of amphiphilic PEG moieties with liposomal bilayer improved lipid membrane permeability to H2O2 and •OH, resulting in efficient initiation of lipid peroxidation and thus ferroptosis in cancer cells. Additionally, Lp-IO enabled traceable magnetic resonance imaging and pH/ROS dual-responsive drug delivery. Synergistic antineoplastic effects of chemotherapy and ferroptosis, and alleviated chemotherapeutic toxicity, were achieved by delivering doxorubicin (capable of xCT and glutathione peroxidase inhibition) with Lp-IO. This work provides an efficient alternative for triggering therapeutic lipid peroxidation and a ferroptosis-activating drug delivery vehicle for combination cancer therapies.
铁死亡是一种由过量脂质过氧化物驱动的铁依赖性调节性细胞死亡过程，可增强肿瘤对化疗、靶向治疗及免疫治疗的敏感性。作为激活铁死亡的关键上游过程，生物膜的脂质过氧化预计主要由双层膜内活性氧（ROS）诱导，这表明通过提高脂质双层中扩散受限的ROS局部含量来引发过氧化是一种前景广阔的策略。本文构建了在双层膜中嵌入聚乙二醇包覆的3纳米γ-三氧化二铁纳米颗粒的脂质体（简称Lp-IO），旨在促进过氧化氢在膜内转化为羟基自由基（•OH）。通过将两亲性聚乙二醇组分与脂质体双层结合，提高了脂质膜对过氧化氢和羟基自由基的渗透性，从而有效启动脂质过氧化并诱导癌细胞铁死亡。此外，Lp-IO还可实现可追踪的磁共振成像及pH/ROS双响应药物递送。通过利用Lp-IO递送多柔比星（可抑制xCT胱氨酸/谷氨酸反向转运蛋白和谷胱甘肽过氧化物酶），实现了化疗与铁死亡的协同抗肿瘤效应，并减轻了化疗毒性。该研究为触发治疗性脂质过氧化提供了高效新途径，并为联合癌症治疗提供了一种铁死亡激活型药物递送载体。
肿瘤(癌症)患者之家