Titanium Dioxide Nanoparticles Trigger Non-Canonical Receptor Endocytosis to Inhibit Wnt Signaling

Biocompatible nanoparticles (NPs) have been implied in various biological and biomedical applications. However, the effects of nanoscale materials on long term health and disease conditions remain largely unclear. Here, we demonstrate that two types of titanium dioxide NPs (TiO₂NPs), with primary sizes of 10 nm and 50 nm, inhibit Wnt signaling under in vitro and in vivo contexts. At concentrations without causing cytotoxicity, TiO₂NPs diminish Wnt-stimulated cancer cell metastasis, weaken the anti-adipogenic effect of Wnt during adipocyte differentiation, and impair Wnt-promoted tail elongation during the development of Zebrafish. Significantly, we find that TiO₂NPs induce non-canonical endocytic trafficking of the Wnt receptor Lrp6. The reduction in the amount of active Lrp6 for signal transduction prevents the nuclear entry of β-catenin, a key transcription activator in the Wnt signaling axis, and interferes with the outputs of Wnt signaling. Our study discloses both potential risks and possible benefits for applications of TiO₂NPs, provides a molecular basis for the interaction between TiO₂NPs and cellular signaling, and suggests close connections between natural biological molecules and synthetic NPs.