NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410078, Hunan, China.
Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha 410078, Hunan, China.
ACS Nano. 2024 Nov 12;18(45):31055-31075. doi: 10.1021/acsnano.4c07676. Epub 2024 Oct 28.
Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck, prevalent in regions such as Southern China and Southeast Asia. Radiotherapy serves as the primary clinical treatment for this carcinoma. However, resistance to radiotherapy is a fundamental cause of treatment failure and patient mortality, with the underlying mechanisms yet to be fully elucidated. We identified a recently characterized circular RNA, circADARB1, which is markedly upregulated in NPC tissues and closely associated with poor prognosis and radiotherapy resistance. Both in vitro and in vivo experiments demonstrated that circADARB1 inhibited ferroptosis, thereby inducing radiotherapy resistance in NPC cells. Building on these findings, we synthesized a biomimetic nanomaterial consisting of semiconducting polymer nanoparticles wrapped in cell membranes, designed to deliver both siRNA targeting circADARB1 and iron ions. The application of this nanomaterial not only efficiently suppressed the expression of circADARB1 and boosted intracellular iron concentrations, but also enhanced ferroptosis induced by radiotherapy, improving the radiosensitivity of NPC cells. Furthermore, our study revealed that circADARB1 upregulated the expression of heat shock protein HSP90B1, which repaired misfolded SLC7A11 and GPX4 proteins triggered by radiotherapy, thereby preserving their stability and biological functions. Mechanistically, SLC7A11 facilitated cysteine transportation into cells and glutathione synthesis, while GPX4 employed glutathione to mitigate intracellular lipid peroxidation induced by radiotherapy, shielding cells from oxidative damage and inhibiting ferroptosis, and ultimately leading to radiotherapy resistance in NPC cells. Our investigation elucidates molecular mechanisms with substantial clinical relevance, highlights the promising application prospects of nanotechnology in precision cancer therapy.
鼻咽癌（NPC）是一种常见的头颈部恶性肿瘤，流行于中国南方和东南亚地区。放射治疗是治疗这种癌症的主要临床方法。然而，放疗抵抗是治疗失败和患者死亡的根本原因，其潜在机制尚未完全阐明。我们发现了一种最近被描述的环状 RNA，circADARB1，它在 NPC 组织中明显上调，与预后不良和放疗抵抗密切相关。体外和体内实验都表明，circADARB1 抑制铁死亡，从而诱导 NPC 细胞产生放疗抵抗。在此基础上，我们合成了一种由细胞膜包裹的半导体聚合物纳米粒子组成的仿生纳米材料，旨在递送靶向 circADARB1 的 siRNA 和铁离子。该纳米材料的应用不仅能有效抑制 circADARB1 的表达，提高细胞内铁浓度，还能增强放疗诱导的铁死亡，提高 NPC 细胞的放射敏感性。此外，我们的研究揭示了 circADARB1 上调热休克蛋白 HSP90B1 的表达，修复放疗引起的 SLC7A11 和 GPX4 蛋白的错误折叠，从而保持其稳定性和生物学功能。从机制上讲，SLC7A11 促进半胱氨酸向细胞内运输和谷胱甘肽合成，而 GPX4 则利用谷胱甘肽减轻放疗引起的细胞内脂质过氧化，使细胞免受氧化损伤，抑制铁死亡，最终导致 NPC 细胞的放疗抵抗。我们的研究阐明了具有重要临床意义的分子机制，突出了纳米技术在精准癌症治疗中的应用前景。
