Magnetic field-controlled nanozymes effectively overcome therapeutic limitations in tumor ferroptosis therapy

Iron oxide nanozymes with intrinsic peroxidase-like activity and excellent biosafety are considered ideal agents for inducing tumor ferroptosis. However, their practical catalytic efficiency is often constrained by an inherent delocalized electronic structure and the restrictive tumor antioxidant microenvironment. Herein, we report a magnetic field-mediated strategy to synthesize ultra-small superparamagnetic manganese-doped iron oxide (USMIO) nanoparticles with precisely tailored multi-enzyme activities (denoted as MUSMIO). The magnetic field in situ generated abundant oxygen vacancies and optimized the Mn/Fe coordination environment, significantly boosting electron transfer and catalytic performance. MUSMIO exhibited robust pH-responsive peroxidase-like activity with a hydroxyl radical yield ∼5.86-fold higher than pure ultra-small superparamagnetic iron oxide (USIO) and ∼2.43-fold higher than USMIO, together with favorable catalase-, glutathione oxidase-, and nicotinamide adenine dinucleotide phosphate oxidase-like activities. This synergistic multi-enzyme cascade efficiently blocked glutathione regeneration, relieved tumor hypoxia, and triggered a sustained hydroxyl radical storm to drive extensive lipid peroxidation and selective ferroptosis in cancer cells, while exhibiting negligible toxicity to normal cells. In a murine breast cancer model, MUSMIO achieved complete tumor regression with no recurrence, and prolonged the median survival time of mice with excellent biosafety. This work provides a generalizable physical-field-assisted route for designing high-performance multi-enzyme mimetic nanozymes for targeted tumor therapy.