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 T
2 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.
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