Copper‐Finger Protein Mimetic Peptide Nanoparticle to Induce Cuproptosis Against Antibiotic‐Resistant Bacteria

Abstract Copper‐induced cell death (cuproptosis) shows great promise against infections, especially antibiotic‐resistant bacteria. However, common copper carriers like inorganic oxides/frameworks suffer from uncontrollable copper ion leakage. Inspired by copper finger protein, similar copper binding peptide with sequence of Met‐Asp‐His‐Gly‐Tyr‐Tyr (MDHGYY) is designed and then forms nanoparticles with copper ions with loading efficiency of 66.5%. To enable controlled release, such peptides are oxidized into melanin‐like nanoparticles by tyrosinase with NIR light responsiveness. The copper‐loaded peptide nanoparticles remain stable without leaking but release copper ions upon NIR irradiation. They can disrupt the pyruvate metabolic pathway within bacteria, inducing dihydrolipoamide S‐acetyltransferase oligomerization with pyruvate upregulation and acetyl‐coenzyme A downregulation for cuproptosis. It also interfere with bacterial quorum sensing, downregulating quorum sensing genes (e.g., agrB, oppA). Overall, synergistic quorum sensing interference and bacterial cuproptosis provide a novel biomimetic strategy against antibiotic‐resistant bacteria, and effectively promte diabetes wound healing.