Because of their unique physicochemical properties, lanthanide-doped upconverting nanoparticles (Ln-UCNPs) have exceptional potential for biological applications. However, the use in biological systems is hampered by the limited understanding of their bionano interactions. Our multidisciplinary study has generated these insights through in-depth and quantitative analyses. The Ln-UCNPs examined here are spherical, monodisperse, and stable in aqueous environments. We show that Ln-UCNPs were associated with HeLa (cervical cancer) and LLC-PK1 (renal proximal tubule) cells and were nontoxic over a wide concentration range. Multiple biomarkers were assessed to monitor the cellular homeostasis in Ln-UCNP-treated cells. To this end, we evaluated the nuclear lamina, nucleoli, and nuclear transport factors. Single-cell analyses quantified the impact on Nrf2 and NF-κB, two transcription factors that control stress and immune responses. Moreover, we measured Ln-UCNP-induced changes in the abundance of molecular chaperones. Collectively, in vitro studies confirmed that Ln-UCNPs are nontoxic and trigger minor cellular stress responses. This lack of toxicity was verified in vivo, using the model organism Caenorhabditis elegans. The compatibility with biological systems prompted us to assess Ln-UCNPs as potential contrast agents for magnetic resonance imaging. We demonstrated that the Ln-UCNPs examined here were especially suitable as T₂ contrast agents; they clearly outperformed the clinically used Gadovist. Taken together, our interdisciplinary work provides robust evidence for the nontoxicity of Ln-UCNPs. This sets the stage for the translation of Ln-UCNP for use in complex biological systems.

中文翻译：

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用于体外和体内应用的镧系元素掺杂上转换纳米粒子的评估

由于其独特的物理化学性质，镧系元素掺杂的上转换纳米粒子 (Ln-UCNPs) 在生物应用方面具有非凡的潜力。然而，在生物系统中的使用受到对其生物纳米相互作用的有限理解的阻碍。我们的多学科研究通过深入和定量分析产生了这些见解。此处检查的 Ln-UCNP 呈球形、单分散且在水环境中稳定。我们表明 Ln-UCNPs 与 HeLa（宫颈癌）和 LLC-PK1（肾近端小管）细胞相关，并且在很宽的浓度范围内无毒。评估多种生物标志物以监测 Ln-UCNP 处理的细胞中的细胞稳态。为此，我们评估了核层、核仁和核转运因子。单细胞分析量化了对 Nrf2 和 NF-κB 这两种控制压力和免疫反应的转录因子的影响。此外，我们测量了 Ln-UCNP 诱导的分子伴侣丰度的变化。集体，体外研究证实，Ln-UCNPs 是无毒的，可引发轻微的细胞应激反应。使用模式生物秀丽隐杆线虫在体内证实了这种毒性的缺乏。与生物系统的兼容性促使我们评估 Ln-UCNPs 作为磁共振成像的潜在造影剂。我们证明了这里检查的 Ln-UCNPs 特别适合作为T ₂造影剂。它们明显优于临床使用的 Gadovist。总之，我们的跨学科工作为 Ln-UCNPs 的无毒提供了有力的证据。这为翻译 Ln-UCNP 以用于复杂的生物系统奠定了基础。