Titanium Nanoparticle Regulates Innate Immunity

In-vivo studies on wound healing have shown that small metal oxide nanoparticles (NPs), such as titania, ferria, and alumina, promote wound closure, likely by enhancing blood coagulation and via activation of the contact system. However, titania differs from the others as it supports the regrowth of normal skin tissue without scarring. This unique effect was hypothesised to result from its ability to suppress inflammation, possibly by interfering with the complement system. Ex-vivo whole blood experiments within the present study confirm that titania NPs significantly dampen the immune response and surface plasmon resonance (SPR) biosensor analysis confirms that the nanoparticle binds with nanomolar affinity to complement C3, a central protein in the human innate immune system. To elucidate the molecular basis of this effect, we developed a novel cryo-electron microscopy (cryo-EM) methodology capable of resolving the challenging interface between metal NPs and proteins. This approach revealed that TiO{square} binds with high specificity to a single domain on C3. The NP restricts the conformational dynamics of C3 and thus blocks the initiation of the complement cascade. These structural and biophysical insights support the biochemical findings and previous observations within the contact system. Our method advancement demonstrates that cryo-EM can uncover physiologically relevant interactions between proteins and nanomaterials at high resolution and offers a strong foundation for others investigating metal-biological interactions.