The present study reports on a comprehensive investigation of mechanisms of in vitro cytotoxicity of high aspect ratio (HAR) bundles formed from anodic TiO2 nanotube (TNT) layers. Comparative cytotoxicity studies were performed using two types of HAR TNTs (diameter of ∼110 nm), differing in initial thickness of the nanotubular layer (∼35 μm for TNTs-1 vs. ∼10 μm for TNTs-2). Using two types of epithelial cell lines (MDA-MB-231, HEK-293), it was found that nanotoxicity is highly cell-type dependent and plausibly associates with higher membrane fluidity and decreased rigidity of cancer cells enabling penetration of TNTs to the cell membrane towards disruption of membrane integrity and reorganization of cytoskeletal network. Upon penetration, TNTs dysregulated redox homeostasis followed by DNA fragmentation and apoptotic/necrotic cell death. Both TNTs exhibited haemolytic activity and rapidly activated polarization of RAW 264.7 macrophages. Throughout the whole study, TNTs-2 possessing a lower aspect ratio manifested significantly higher cytotoxic effects. Taken together, this is the first report comprehensively investigating the mechanisms underlying the nanotoxicity of bundles formed from self-organised 1-D anodic TNT layers. Except for description of nanotoxicity of industrially-interesting nanomaterials, the delineation of the nanotoxicity paradigm in cancer cells could serve as solid basis for future efforts in rational engineering of TNTs towards selective anticancer nanomedicine.

Center of Materials and Nanotechnologies Faculty of Chemical Technology University of Pardubice Nam Cs Legii 565 CZ 530 02 Pardubice Czechia

Central European Institute of Technology Brno University of Technology Purkynova 656 123 CZ 612 00 Brno Czechia; Center of Materials and Nanotechnologies Faculty of Chemical Technology University of Pardubice Nam Cs Legii 565 CZ 530 02 Pardubice Czechia

Research Group for Molecular Biology and Nanomedicine Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 CZ 613 00 Brno Czechia

Research Group for Molecular Biology and Nanomedicine Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 CZ 613 00 Brno Czechia; Central European Institute of Technology Brno University of Technology Purkynova 656 123 CZ 612 00 Brno Czechia

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