Tumor microenvironments self-activated cascade catalytic nanoscale metal organic frameworks as ferroptosis inducer for radiosensitization

Radioresistance has always been a major factor for radiotherapy failure. Ferroptosis, as a form of nonapoptotic programmed cell death, has been recently found being closely associated with radioresistance. The application of ferroptosis inducer might be an efficient strategy to resensitize radiotherapy. Herein, novel tumor microenvironments (TME) activated metal-organic frameworks involving Fe & Cu dual ions bridged through disulfide bonds with PEGylation (FCSP MOFs) were applied as ferroptosis inducer, which could induce ferroptosis by synergetic Fenton/Fenton-like reaction and glutathione (GSH)-depletion assistant glutathione peroxidase 4 (GPX4) inactivation. Inspired by the glucose oxidase-mimicking property of Au NPs, Au NPs were in situ grown on FCSP MOFs (AuFCSP MOFs) to further enhance the inducing efficiency, which could assist conversion of intratumoral over-uptake glucose into gluconic acid and toxic H2O2 and cascade react with Fenton/Fenton-like reaction. Both in vitro and in vivo experiments demonstrated that the AuFCSP MOFs could significantly enhance the therapeutic efficiency of radiotherapy by taking the synergistic effect of efficient ferroptosis inducing and high-Z element enhancing. The relevance between AuFCSP MOFs ferroptosis inducer and radiotherapy was also discussed.