MoS 2 ‐Doped Iron Oxide Nanozyme with Co‐Catalytic Enhancement for Tumor Ferroptosis Guided by Magnetic Resonance Imaging

ABSTRACT Fe 3 O 4 nanoparticles exhibit therapeutic and diagnostic capabilities by inducing ferroptosis through reactive oxygen species generated by the Fenton reaction and enhancing magnetic resonance imaging (MRI) contrast. However, the efficacy of ferroptosis induced by Fe 3 O 4 is limited by several factors, including low Fe 2+ concentration, restricted Fenton‐active sites, excessive glutathione (GSH), and insufficient acidity of tumor cells. In this study, MoS 2 ‐doped Fe 3 O 4 , with peroxidase and glutathione oxidase‐like activities, was functionalized with tamoxifen (TAM) and coated with bovine serum albumin (BSA) to construct Fe 3 O 4 /MoS 2 @TAM/BSA (FMTB) nanoparticles. The incorporation of MoS 2 facilitated the generation of abundant oxygen vacancies, which increased the number of active sites, acted as a co‐catalyst to accelerate the reduction of Fe 3+ to Fe 2+ , and promoted GSH consumption, resulting in a 51.3% increase in Fenton activity and a 4.3‐fold enhancement in GSH consumption compared to Fe 3 O 4 alone. The released TAM inhibited mitochondrial complex I and improved tumor cellular acidity, thereby creating a conducive environment for the Fenton reaction. By enhancing peroxidase‐like activity through co‐catalysis and reducing cellular pH, FMTB achieved a 70.6% tumor growth inhibition, in contrast to the 20.8% inhibition observed with Fe 3 O 4 alone. Furthermore, the FMTB‐mediated tumor T 2 ‐weighted MRI signal was attenuated by 17% compared to that of Fe 3 O 4 . Thus, this multienzyme‐based platform presents a novel strategy for highly efficient ferroptosis therapy against tumors by enhancing Fenton reaction efficiency and depleting GSH.