Nanomaterials hold great promise for applications in the delivery of various molecules with poor cell penetration, yet its potential for delivery of metal ions is rarely considered. Particularly, there is limited insight about the cytotoxicity triggered by nanoparticle-ion interactions. Oxidative stress is one of the major toxicological mechanisms for nanomaterials, and we propose that it may also contribute to nanoparticle-ion complexes induced cytotoxicity. To explore the potential of nanodiamonds (NDs) as vehicles for metal ion delivery, we used a broad range of experimental techniques that aimed at getting a comprehensive assessment of cell responses after exposure of NDs, metal ions, or ND-ion mixture: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Trypan blue exclusion text, optical microscope observation, synchrotron-based scanning transmission X-ray microscopy (STXM) and micro X-ray fluorescence (μXRF) microscopy, inductively coupled plasma-mass spectrometry (ICP-MS), reactive oxygen species (ROS) assay and transmission electron microscopy (TEM) observation. In addition, theoretical calculation and molecular dynamics (MD) computation were used to illustrate the adsorption properties of different metal ion on NDs as well as release profile of ion from ND-ion complexes at different pH values. The adsorption capacity of NDs for different metal ions was different, and the adsorption for Cu2+ was the most strong among divalent metal ions. These different ND-ion complexes then had different cytotoxicity by influencing the subsequent cellular responses. Detailed investigation of ND-Cu2+ interaction showed that the amount of released Cu2+ from ND-Cu2+ complexes at acidic lysosomal conditions was much higher than that at neutral conditions, leading to the elevation of intracellular ROS level, which triggered cytotoxicity. By theoretical approaches, we demonstrated that the functional carbon surface and cluster structures of NDs made them good vehicles for metal ions delivery. NDs played the Trojan horse role by allowing large amounts of metal ions accumulate into living cells followed by subsequent release of ions in the interior of cells, which then led to cytotoxicity. The present experimental and theoretical results provide useful insight into understanding of cytotoxicity triggered by nanoparticle-ion interactions, and open new ways in the interpretation of nanotoxicity.

中文翻译：

---

纳米金刚石充当特洛伊木马，用于细胞内传递金属离子以触发细胞毒性。

纳米材料在输送细胞渗透性差的各种分子方面具有广阔的前景，但很少考虑其输送金属离子的潜力。特别地，关于由纳米粒子-离子相互作用触发的细胞毒性的见解有限。氧化应激是纳米材料的主要毒理学机制之一，我们建议它也可能有助于纳米粒子-离子复合物诱导的细胞毒性。为了探索纳米金刚石（NDs）作为金属离子传递媒介的潜力，我们使用了广泛的实验技术，旨在对NDs，金属离子或ND离子混合物暴露后的细胞反应进行全面评估：3- （4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物（MTT）测定，锥虫蓝排除法，光学显微镜观察，基于同步加速器的扫描透射X射线显微镜（STXM）和显微X射线荧光（μXRF）显微镜，电感耦合等离子体质谱（ICP-MS），活性氧（ROS）测定和透射电子显微镜（TEM）观察。此外，通过理论计算和分子动力学（MD）计算来说明不同金属离子在NDs上的吸附特性，以及在不同pH值下ND离子络合物中离子的释放曲线。NDs对不同金属离子的吸附能力不同，并且在二价金属离子中对Cu2 +的吸附最强。然后，这些不同的ND离子复合物通过影响随后的细胞反应而具有不同的细胞毒性。对ND-Cu2 +相互作用的详细研究表明，在酸性溶酶体条件下从ND-Cu2 +复合物中释放的Cu2 +量远高于在中性条件下，导致细胞内ROS水平升高，从而触发了细胞毒性。通过理论方法，我们证明了ND的功能性碳表面和簇结构使其成为金属离子传递的良好载体。ND通过使大量金属离子积累到活细胞中，随后在细胞内部释放离子，从而导致细胞毒性，从而起到了特洛伊木马的作用。目前的实验和理论结果为了解由纳米粒子-离子相互作用触发的细胞毒性提供了有用的见识，并为解释纳米毒性开辟了新途径。