Europium-doped Gd2O3 nanotubes cause the necrosis of primary mouse bone marrow stromal cells through lysosome and mitochondrion damage

With the wide applications of europium-doped Gd 2 O 3 nanoparticles (Gd 2 O 3 :Eu 3   + NPs) in biomedical fields, it will inevitably increase the chance of human exposure. It was reported that Gd 2 O 3 :Eu 3   + NPs could accumulate in bone. However, there have been few reports about the potential effect of Gd 2 O 3 :Eu 3   + NPs on bone marrow stromal cells (BMSCs). In this study, the Gd 2 O 3 :Eu 3   + nanotubes were prepared and characterized by powder X-ray diffraction (XRD), photoluminescence (PL) excitation and emission spectra, scanning electron microscope (SEM), and transmission electron microscopy (TEM). The cytotoxicity of Gd 2 O 3 :Eu 3   + nanotubes on BMSCs and the associated mechanisms were further studied. The results indicated that they could be uptaken into BMSCs by an energy-dependent and macropinocytosis-mediated endocytosis process, and primarily localized in lysosome . Gd 2 O 3 :Eu 3   + nanotubes effectively inhibited the viability of BMSCs in concentration and time-dependent manners. A significant increase in the percentage of late apoptotic/necrotic cells, lactate dehydrogenase (LDH) leakage and the number of PI-stained cells was found after BMSCs were treated by 10, 20, and 40   μg/mL of Gd 2 O 3 :Eu 3   + nanotubes for 12   h. No obvious DNA ladders were detected, but a dispersed band was observed. The above results revealed that Gd 2 O 3 :Eu 3   + nanotubes could trigger cell death by necrosis instead of apoptosis. Two mechanisms were involved in Gd 2 O 3 :Eu 3   + nanotube-induced BMSCs necrosis: lysosomal rupture and release of cathepsins B ; and the overproduction of reactive oxygen species (ROS) injury to the mitochondria and DNA. The study provides novel evidence to elucidate the toxicity mechanisms and may be beneficial to more rational applications of these nanomaterials in the future.