Cytotoxicity and RNA-sequencing analysis of macrophages after exposure to vanadium dioxide nanoparticles

Extensive applications of vanadium dioxide (VO 2 )-based materials raise concerns over the biosafety of VO 2 exposure via various routes. To understand the effects of VO 2 on people's health, we used RNA sequencing (RNA-seq) to monitor the widespread changes in gene expression to reveal the toxicity mechanism of two commercial VO 2 materials, nanoscale VO 2 (S-VO 2 ) and bulk VO 2 (M-VO 2 ), on the RAW264.7 cell line, which represents the first cellular systems dealing with xenobiotics. Nanoscale S-VO 2 displayed higher toxicity than bulk M-VO 2 , but both VO 2 particles inhibited the proliferation and induced apoptosis in RAW264.7 cells with similar toxicity mechanisms. As shown by RNA-seq analysis and validated by biochemical assays, VO 2 particles induced endoplasmic reticulum stress accompanied by the release of calcium ions and the overproduction of reactive oxygen species, leading to DNA damage, mitochondrial damage, autophagy and lysosomal damage, which finally resulted in apoptosis and proliferation inhibition, showing a decline in viability. The cellular uptake of VO 2 particles and the dissolved species of VO 2 jointly contributed to the observed toxicity. This systematic study reveals the toxicity mechanisms of VO 2 materials at the transcriptome level, providing valuable data for their safe applications in the future. VO 2 NPs trigger endoplasmic reticulum stress, release of calcium ions, and overproduction of ROS, leading to a significant proliferation inhibition and apoptosis in macrophages. VO 2 NPs display higher responses and toxicity than bulk VO 2 .