Iron (II)-based metal-organic framework nanozyme for boosting tumor ferroptosis through inhibiting DNA damage repair and system Xc-

Abstract Development of ferroptosis-inducible nanoplatforms with high efficiency and specificity is highly needed and challenging in tumor ferrotherapy. Here, we demonstrate highly effective tumor ferrotherapy using iron (II)-based metal-organic framework (Fe ss MOF) nanoparticles, assembled from disulfide bonds and ferrous ions. The as-prepared Fe ss MOF nanoparticles exhibit peroxidase-like activity and pH/glutathione-dependent degradability, which enables tumor-responsive catalytic therapy and glutathione depletion by the thiol/disulfide exchange to suppress glutathione peroxidase 4, respectively. Upon PEGylation and Actinomycin D (ActD) loading, the resulting Fe ss MOF/ActD-PEG nanoplatform induces marked DNA damage and lipid peroxidation. Concurrently, we found that ActD can inhibit Xc − system and elicit ferritinophagy, which further boosts the ferrotherapeutic efficacy of the Fe ss MOF/ActD-PEG. In vivo experiments demonstrate that our fabricated nanoplatform presents excellent biocompatibility and a high tumor inhibition rate of 91.89%.