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Yi Zhen Tan,1 Lucy R Thomsen,1 Nensi Shrestha,1 Adalberto Camisasca,2 Silvia Giordani,2 Rhonda Rosengren1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, 9016, New Zealand; 2School of Chemical Sciences, Dublin City University, Glasnevin, Dublin, D09 NA55, IrelandCorrespondence: Rhonda Rosengren, Department of Pharmacology and Toxicology, 18 Frederick Street, Dunedin, 9016, New Zealand, Tel +64 3 479 9141, Fax +64 3 479 9140, Email rhonda.rosengren@otago.ac.nzBackground: A nanoscale drug carrier could have a variety of therapeutic and diagnostic uses provided that the carrier is biocompatible in vivo. Carbon nano-onions (CNOs) have shown promising results as a nanocarrier for drug delivery. However, the systemic effect of CNOs in rodents is unknown. Therefore, we investigated the toxicity of CNOs following intravenous administration in female BALB/c mice.Results: Single or repeated administration of oxi-CNOs (125, 250 or 500 μg) did not affect mouse behavior or organ weight and there was also no evidence of hepatotoxicity or nephrotoxicity. Histological examination of organ slices revealed a significant dose-dependent accumulation of CNO aggregates in the spleen, liver and lungs (p< 0.05, ANOVA), with a trace amount of aggregates appearing in the kidneys. However, CNO aggregates in the liver did not affect CYP450 enzymes, as total hepatic CYP450 as well as CYP3A catalytic activity, as meased by erythromycin N-demethylation, and protein levels showed no significant changes between the treatment groups compared to vehicle control. CNOs also failed to act as competitive inhibitors of CYP3A in vitro in both mouse and human liver microsomes. Furthermore, CNOs did not cause oxidative stress, as indicated by the unchanged malondialdehyde levels and superoxide dismutase activity in liver microsomes and organ homogenates.Conclusion: This study provides the first evidence that short-term intravenous administration of oxi-CNOs is non-toxic to femal