Photothermia at the nanoscale induces ferroptosis via nanoparticle degradation

Iron oxide magnetic nanoparticles are utilized in Fe(II)-induced ferroptosis for cancer therapy, but controlling the Fe(II) release from magnetic nanoparticles remains challenging. Here the authors reveal that photothermia at the nanoscale can remotely trigger the degradation of magnetic nanoparticles, leading to Fe(II) release and a synergistic photothermo-ferroptotic therapy. The Fe(II)-induced ferroptotic cell death pathway is an asset in cancer therapy, yet it calls into question the biocompatibility of magnetic nanoparticles. In the latter, Fe(II) is sequestered within the crystal structure and is released only upon nanoparticle degradation, a transition that is not well understood. Here, we dissect the chemical environment necessary for nanoparticle degradation and subsequent Fe(II) release. Importantly, temperature acts as an accelerator of the process and can be triggered remotely by laser-mediated photothermal conversion, as evidenced by the loss of the nanoparticles' magnetic fingerprint. Remarkably, the local hot-spot temperature generated at the nanoscale can be measured in operando, in the vicinity of each nanoparticle, by comparing the photothermal-induced nanoparticle degradation patterns with those of global heating. Further, remote photothermal irradiation accelerates degradation inside cancer cells in a tumor spheroid model, with efficiency correlating with the endocytosis progression state of the nanoparticles. High-throughput imaging quantification of Fe2+ release, ROS generation, lipid peroxidation and cell death at the spheroid level confirm the synergistic thermo-ferroptotic therapy due to the photothermal degradation at the nanoparticle level.

Automated summary

This study demonstrates that photothermia at the nanoscale can trigger the degradation of magnetic nanoparticles, leading to the release of Fe(II) and enabling photothermo-ferroptotic therapy. The temperature acts as an accelerator for nanoparticle degradation and can be remotely triggered by laser-mediated photothermal conversion. The efficacy of this treatment method has been confirmed in in vitro experiments.