Self-Cycling Free Radical Generator from LDH-Based Nanohybrids for Ferroptosis-Enhanced Chemodynamic Therapy

Nonapoptotic ferroptosis has been a novel form ofprogrammed cell death, which provides a new solution to enrich the anticancer treatment efficacy of traditional apoptotic therapeutic modality. Herein, a novel nanohybrid is designed by loading the PEG-encapsulated Artemisinin (denoted as A@P) on the ultrathin MgFe-LDH nanosheets (denoted as uLDHs) for improved chemodynamic therapy (CDT). The A@P/uLDHs cannot only realize the self-assembly between the Art and carrier but also be regarded as free radical generator. A comprehensive mechanistic study suggests that this unique A@P/uLDHs is able to in situ activate Art and self-cycling generate toxic C-centered free radical inside the cancer cells, without depending on abundant H2O2, accompanied with diminished cancerous antioxidation by depleting glutathione (GSH). The accumulation ofROS and depletion ofGSH can further oxidize unsaturated fatty acid to generate lipid peroxide, whose overexpression can induce cell ferroptosis accompanied by cellular iron homeostasis turbulence. Both in vitro and in vivo results exhibit that A@P/uLDHs are an efficient nanoagent for highly efficient ferroptosis-enhanced CDT treatment. This work imparts the promising new visions about the ferroptosis-enhanced CDT via fine regulation ofmaterial design for improved cancer treatments.

非凋亡性铁死亡（ferroptosis）是一种新型程序性细胞死亡形式，为优化传统凋亡类抗癌治疗手段的疗效提供了全新思路。本研究设计了一种新型纳米杂化物：将聚乙二醇（PEG）包被的青蒿素（Artemisinin，缩写为A@P）负载于超薄MgFe层状双氢氧化物纳米片（MgFe-LDH，缩写为uLDHs）上，以增强化学动力学治疗（chemodynamic therapy，CDT）效果。该A@P/uLDHs体系不仅可实现青蒿素与载体的自组装，同时可作为自由基发生器发挥作用。全面的机制研究表明，该独特的A@P/uLDHs可在癌细胞内原位激活青蒿素，并通过自循环过程生成具有细胞毒性的碳中心自由基，且无需依赖高浓度过氧化氢（H₂O₂）；同时可通过消耗谷胱甘肽（glutathione，GSH）削弱癌细胞的抗氧化能力。活性氧（reactive oxygen species，ROS）的积累与谷胱甘肽的耗竭可进一步氧化不饱和脂肪酸，生成脂质过氧化物；脂质过氧化物的过量积累可诱导细胞铁死亡，并伴随细胞铁稳态紊乱。体外与体内实验结果均证实，A@P/uLDHs是一种高效纳米制剂，可用于实现高效的铁死亡增强型化学动力学治疗。本研究通过精准调控材料设计实现铁死亡增强型化学动力学治疗，为癌症治疗的优化提供了极具前景的全新思路。