Whittaker, J. J.; Eikrem, D.; Seisenbaeva, G. A.; Fromell, K.; Ekdahl, K. N.; Nilsson, B.; Sandgren, M.; Kessler, V. G.

Titanium dioxide (TiO2) nanoparticles, widely incorporated in everyday products such as food additives (E171), cosmetics, confectionary and paints, represent one of the most prevalent forms of engineered metal-based nanoparticles (MNPs) in modern environments. Despite their ubiquity, safety data on their immunological impact remains limited. Of particular concern are sub-5 nm TiO2 nanoparticles, which possess the capacity to cross cellular barriers and disrupt protein function. This study investigates the interaction between 3.5 nm triethanolamine-terminated TiO2 nanoparticles and complement C3, a central protein in the human innate immune system. Using cryo-electron microscopy, we reveal direct binding of TiO2 nanoparticles to the surface of C3, leading to structural restrictions that hinder its activation and subsequent complement cascade progression. Biochemical and haemolytic assays confirm that these nanoparticles act as alternative pathway-specific inhibitors, impairing normal immune function. These findings underscore the potential immunomodulatory effects of TiO2 nanoparticles and highlight the need for thorough evaluation of their biological impact, particularly given their widespread human exposure.