Nanodiamonds improve arsenic trioxide treatment of liver tumor by inhibiting metastasis in multiple organs

Arsenic trioxide (ATO)-based therapy has demonstrated high potency in treating leukemia but limited efficacy in solid tumors. Here we report a potent multiple organ-specific anti-metastatic mechanism of nanodiamonds (NDs) in ATO-based therapy for liver cancer, which is characterized by its high metastatic potential that underlies the cause for cancer-related death. In a liver tumor mouse model, NDs co-treatment effectively inhibited the ATO-associated metastasis of liver cancer in the liver, spleen, and intestines, with inhibition potencies closely correlated with the biodistribution of NDs among different organs. Consequently, NDs co-treatment improved the survival rate of ATO-treated mice from 0% to 100% during 135–174 days from the initiation of therapy, with ∼ 20% survival of mice for over 10 months. Mechanistically, NDs co-treatment inhibited autophagy by upregulating LC3-II and p62, thereby inhibiting metastasis dissemination by inactivating the TGF-β/Smad3 pathway. Our study unravels a potentially generalizable strategy for inhibiting multiple-organ cancer metastasis via nanoparticle-mediated modulation of autophagy. [Display omitted] •Nanodiamonds (NDs) inhibited the arsenic trioxide (ATO) -associated metastasis in multiple organs.•Inhibition potencies were closely correlated with the biodistribution of NDs.•Co-treatment improved the survival rate of mice from 0% to 100% during 135–174 days.•Co-treatment led to ∼ 20% survival of mice for over 10 months.•Multiple-organ metastasis inhibition was regulated by NDs-mediated autophagy modulation.