Copper‐Doped Prussian Blue Nanozymes: Targeted Starvation Therapy Against Gram‐Positive Bacteria via the ABC Transporter Inhibition

Abstract Nonspecific bactericidal agents often damage host cells and exhibit off‐target toxicity, while existing bacteria‐targeting strategies face challenges in complexity, cost, and compromised efficacy. This study introduces copper‐doped Prussian blue (CuPB) nanozymes that selectively eradicate Gram‐positive bacteria through a novel starvation therapy mechanism. By leveraging the coordination between Cu ²⁺ and abundant peptide bonds in the thick peptidoglycan layer of Gram‐positive bacteria, CuPB achieves specific bacterial adhesion. It disrupts nutrient transport by inhibiting ATP‐binding cassette (ABC) transporters‐critical membrane proteins for bacterial metabolism‐while simultaneously deploying multienzyme‐like activities (oxidase, peroxidase, glutathione peroxidase) to generate reactive oxygen species (ROS) and release antibacterial metal ions. Transcriptomic analysis confirms CuPB's suppression of ABC transporter‐related genes in methicillin‐resistant Staphylococcus aureus ( MRSA ), effectively starving bacteria and enhancing ROS/metal ion lethality. Remarkably, CuPB demonstrates broad‐spectrum Gram‐positive antibacterial activity, biofilm inhibition, and excellent biosafety in vitro/vivo. This work pioneers a synergistic targeting‐strategy combining metabolic interference, enzymatic catalysis, and ion release, offering a translatable paradigm for precision antimicrobial therapy.