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

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 Fe²⁺ 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 Fe²⁺ 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/Fe²⁺-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.