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Intensive investigations have been devoted to lanthanide-doped upconversion nanoparticles (UCNPs), which have shown great potential in applications such as biomedical imaging and therapy. Recently, various polymer-coated UCNPs, as novel bioprobes or nanocarriers, have been developed and their cellular uptake behavior and cytotoxicity have been widely studied. However, the interactions between the UCNPs and subcellular organelles are poorly understand, which restrict their applications in biomedicine. Herein, we engineered UCNPs with different surface charges (positive, negative, and neutral) and studied the dependence between cytotoxicity, internalization, and subcellular localization in normal and cancer cell lines. It was observed that UCNPs with positive or neutral charges entered most of the studied cell lines, whereas UCNPs with negative charges internalize mostly inside the cancer cell lines. Moreover, upon entering into the cells, these UCNPs are localized in different cell compartments, e.g. the cytoplasm, mitochondria or lysosomes, depending on their surface charges and incubation time with the cells. It is revealed that the cytotoxicity of the differently charged UCNPs towards the studied cell lines significantly depends on localization in the mitochondria rather than in the lysosomes or cytoplasm. The corresponding changes in the mitochondria structure were visualized showing the likelihood of cell death. These results have enriched our knowledge on the cytotoxicity of UCNPs in organelle and sheds light on the design of organelle-targeted UCNPs in tumor imaging and therapy.

Dependence between cytotoxicity and dynamic subcellular localization of up-conversion nanoparticles with different surface charges