TiO₂ nanoparticles promote tumor metastasis by eliciting pro-metastatic extracellular vesicles

The development of nanotechnology has provided numerous possibilities for the diagnosis and treatment of cancer. Paradoxically, some in vivo experimental studies have also shown that nanoparticles (NPs) could promote tumor progression, but the specific mechanism is not yet clear. Primary tumors can release extracellular vesicles (EVs) which can promote the inoculation and growth of tumor cells that have metastasized to distant organs. So, whether nanomaterials can promote tumor progression through tumor-derived EVs deserves further research. Here, we showed that TiO₂ NPs, widely used in nanomedicine, could trigger tumor-derived EVs with enhanced pro-metastatic capacity in vitro and in vivo. Mechanically, miR-301a-3p derived from NPs-elicited EVs could be delivered into vascular endothelial cells, which inhibited the expression of VEGFR2 and VE-cadherin by targeting S1PR1, leading to disrupt the tight junctions of vascular endothelial cells, thus to promote vascular permeability and angiogenesis, and induce the formation of pre-metastasis niches in vivo. This study emphasizes that it is urgent to consider the effect of NPs on EVs under long-term use conditions when designing nanodrugs for cancer treatment.