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

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.