Blue light-triggered Fe2+-release from monodispersed ferrihydrite nanoparticles for cancer iron therapy.

Abstract Site-specific Fe2+ generation is promising for tumor therapy. Up to now, reported materials or systems for Fe2+ delivery do not naturally exist in the body, and their biological safety and toxicity are concerned. Herein, inspired by the natural biomineral ferrihydrite in ferritin , we synthesized monodispersed ferrihydrite nanoparticles and demonstrated a light triggered Fe 2+ generation on tumor sites. Ferrihydrite nanoparticles of 20–30 nm in diameter possessed high cellular uptake efficiency and good biocompatibility . Under common blue light illumination, a large amount of Fe 2+ could be released from ferrihydrite and promote the iron/reactive oxygen species (ROS)-related irreversible DNA fragmentation and glutathione peroxidase 4 (GPX4) inhibition, which led to the apoptosis- and ferroptosis-depended cancer cell proliferation inhibition. On mice, this method induced tumor associated macrophage (TAM) polarization from the tumor-promoting M2 type to the tumor-killing M1 type. With the intravenous pre-injection of ferrihydrite, the combinational effects of the light/Fe 2+-approach attenuated pulmonary metastasis on mice. These results demonstrated a novel external light controlled Fe2+-generation approach based on biomineral, which will fully tap the anti-cancer potential of Fe2+ in chemo-dynamic, photo-dynamic and immune-activating therapies.