Symmetry breaking unlocks superior reactivity in single atom catalytic therapy

Single atom enzymes (SAEs) serve as promising alternatives to natural enzymes in therapeutic applications due to their simple structure and strong catalytic performance. However, their activity often lags native enzymes, limiting their practical utility. Although synergistic strategies involving auxiliary drugs or molecular partners can improve therapeutic outcomes, the added complexity hinders translational feasibility. Therefore, enhancing SAE reactivity without introducing additional components remains a critical challenge. Here, inspired by the asymmetric coordination architectures of natural metalloenzymes, we introduce a biomimetic Mn-S₁N₃ coordination environment to break the intrinsic symmetry of conventional Mn-N₄ SAEs. The incorporation of a single sulfur atom triggers localized electronic polarization, reconfigures the Mn orbital alignment, and generates an internal electric field that facilitates intermediate adsorption and bond activation. This coordination tuning significantly lowers the energy barrier for the oxidation of hydrogen peroxide and glutathione, leading to enhanced catalytic performance. Both experimental and DFT studies demonstrate that Mn-S₁N₃ outperforms its symmetric Mn-N₄ counterpart, effectively driving irreversible tumor ferroptosis. This work presents a symmetry-breaking design strategy that bridges the performance gap between artificial and natural enzymes, providing a streamlined and translatable solution for single atom catalytic therapy.