Engineering Strain‐Defects to Enhance Enzymatic Therapy and Induce Ferroptosis

Abstract The effect of mimetic enzyme catalysis is often limited by insufficient activity and a single therapy is not sufficient to meet the application requirements. In this study, a multifunctional nanozyme, MMSR‐pS‐PEG, is designed and fabricated by modifying poly (ethylene glycol) grafted phosphorylated serine (pS‐PEG) on mesoporous hollow MnMoO x spheres, followed by loading sorafenib (SRF) into the pores. Strain engineering‐induced oxygen defects endow the nanozyme with enhanced dual‐enzymatic activity to mimic catalase and oxidase‐like activities, which catalyze the conversion of endogenous H 2 O 2 into oxygen and subsequently into superoxide ions in the acidic tumor microenvironment. Moreover, as an n‐type semiconductor, MnMoO x generates reactive oxygen species by separating electrons and holes upon ultrasonic irradiation and simultaneously deplete glutathione by holes, thereby further augmenting its catalytic effect. As a ferroptosis inducer, SRF restrains the system x c − and indirectly inhibits glutathione synthesis, synergistically interacting with the nanozyme to stimulate ferroptosis by promoting lipid peroxidation and accumulation and the downregulation of glutathione peroxidase 4. These results provide valuable insights into the design of enzymatic therapy with high performance and highlight a promising approach for the synergism of ferroptosis and enzymatic tumor therapy.