Photothermia at the nanoscale induces ferroptosis via nanoparticle degradation

Abstract The Fe(II)-induced ferroptotic cell death pathway has contrasted the biocompatibility of magnetic nanoparticles while offering an additional asset in cancer therapy. Nevertheless, in magnetic nanoparticles, Fe(II) is sequestered within the crystal structure, and for it to become active the nanoparticles must be degraded, a transition that is not well understood. Here, the chemical environment necessary for nanoparticle degradation and subsequent Fe(II) release is dissected. Importantly, it is evidenced that temperature acts as 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 could be measured in operando, in the vicinity of each nanoparticle, by comparing the laser-induced nanoparticle degradation patterns with those of global heating. Further, remote laser exposure also acts as a degradation accelerator inside cancer cells in a tumor spheroid model, with efficiency correlating with the endocytosis progression state of the nanoparticles. High-throughput imaging quantification of Fe(II) release and cell death at spheroid level confirmed the synergistic thermo-ferroptotic therapy due to the laser-induced hot-spot-mediated degradation at the nanoparticles level.