放射动力学疗法（RDT）能在X射线刺激下产生1O2和其他反应性氧化物（ROS），可与放射治疗（RT）结合使用，在显著降低X射线剂量和减少传统放射治疗所带来的放射性抗药性方面得到应用。然而，在实体肿瘤的低氧环境下，放射-放射动力学治疗（RT-RDT）仍然是无效的，因为它依赖于氧分子。化学动力学疗法（CDT）可以通过分解低氧细胞中的H2O2来产生反应性氧化物和O2，从而增强RT-RDT的协同作用。在此，我们开发了多功能纳米系统AuCu-Ce6-TPP（ACCT），用于RT-RDT-CDT。通过Au-S键将Ce6光敏剂连接到AuCu纳米颗粒上实现放射动力学增敏。Cu能够被H2O2氧化，并通过类Fenton反应催化降解H2O2生成•OH来实现CDT。同时，降解产物氧气可以缓解低氧状态，Au能够消耗谷胱甘肽以增加氧化应激。然后，我们将巯基乙基三苯基膦（TPP-SH）连接到纳米系统上，将ACCT定位于线粒体（共定位Pearson系数为0.98），直接破坏线粒体膜并更有效地诱导细胞凋亡。我们证实，ACCT能够在正氧和低氧的4T1细胞中通过X射线照射有效产生1O2和•OH，从而产生强烈的抗癌功效。降低缺氧诱导因子1α表达和减少细胞内H2O2浓度表明，ACCT能够显著缓解4T1细胞中的低氧状态。ACCT增强的RT-RDT-CDT能够在4 Gy的X射线照射下成功缩小或清除放射性抗药性4T1肿瘤携带的小鼠肿瘤。因此，我们提出了一种治疗放射性抗药性低氧肿瘤的新策略。

Radiodynamic therapy (RDT), which produces 1O2 and other reactive oxygen species (ROS) in response to X-rays, can be used in conjunction with radiation therapy (RT) to drastically lower X-ray dosage and reduce radio resistance associated with conventional radiation treatment. However, radiation-radiodynamic therapy (RT-RDT) is still impotent in a hypoxic environment in solid tumors due to its oxygen-dependent nature. Chemodynamic therapy (CDT) can generate reactive oxygen species and O2 by decomposing H2O2 in hypoxic cells and thus potentiate RT-RDT to achieve synergy. Herein, we developed a multifunctional nanosystem, AuCu-Ce6-TPP (ACCT), for RT-RDT-CDT. Ce6 photosensitizers were conjugated to AuCu nanoparticles via Au-S bonds to realize radiodynamic sensitization. Cu can be oxidized by H2O2 and catalyze the degradation of H2O2 to generate •OH through the Fenton-like reaction to realize CDT. Meanwhile, the degradation byproduct oxygen can alleviate hypoxia while Au can consume glutathione to increase the oxidative stress. We then attached mercaptoethyl-triphenylphosphonium (TPP-SH) to the nanosystem, targeting ACCT to mitochondria (colocalization Pearson coefficient 0.98) to directly disrupt mitochondrial membranes and more efficiently induce apoptosis. We confirmed that ACCT efficiently generates 1O2 and •OH upon X-ray irradiation, resulting in strong anticancer efficacy in both normoxic and hypoxic 4T1 cells. The down-regulation of hypoxia-inducible factor 1α expression and reduction of intracellular H2O2 concentrations suggested that ACCT could significantly alleviate hypoxia in 4T1 cells. ACCT-enhanced RT-RDT-CDT can successfully shrink or remove tumors in radioresistant 4T1 tumor-bearing mice upon 4 Gy of X-ray irradiation. Our work thus presents a new strategy to treat radioresistant hypoxic tumors.