A heterovalent single-atom bioorthogonal nanozyme engineered via metal-phenolic networks for potent antimicrobial therapy

Single-atom nanozymes (SAzymes) are emerging as superior alternatives to conventional nanozymes for antibacterial therapy and other biomedical applications, owing to their well-defined structures, unambiguous catalytic sites and exceptional catalytic activities. However, constructing tailored multicomponent SAzymes with mixed-valence state catalytic units remains challenging. Herein, we present a heterovalent FeN₄-Cu⁰ bioorthogonal nanozyme engineered from metal-phenolic networks. This unique architecture compartmentalizes distinct catalytic functions: The FeN₄ single atoms exhibit high peroxidase-like activity to catalyze the generation of hydroxyl radicals (·OH), while the Cu⁰ clusters activate antimicrobial molecules via click chemistry. Meanwhile, the spiky morphology of FeN₄-Cu⁰ potentiates the antibacterial efficacy by physically trapping bacteria, thereby enabling the localized synergistic sterilization through reactive oxygen species and activated drugs. Combined experimental and mechanistic studies demonstrate that this system achieves remarkable antibacterial efficacy by disrupting the bacterial membrane structure, inhibiting biosynthesis and metabolism, inducing oxidative stress, and disrupting energy metabolism. This work provides a feasible strategy for constructing customizable single-atom bioorthogonal nanozymes with mixed oxidation-state catalytic units.