Self‐Assembled Zinc–Polyphenol–Polypeptide Nanocomplexes for Enhanced Bacterial Eradication

ABSTRACT Transition metal ions such as Ag + , Cu 2+ , and Zn 2+ are widely used as antimicrobial agents. However, effectively deploying metal ions for antibacterial therapy in vivo remains challenging, as they are prone to deactivation in complex physiological conditions. In this study, due to the relatively low cytotoxicity of Zn 2+ , we fabricate a nanocarrier of Zn 2+ by one‐step coordination self‐assembly of Zn 2+ , ε‐poly( l ‐lysine) (EPL), and protocatechuic acid (PA). The Zn 2+ –PA–EPL nanocomplexes (ZPE NCs) can adhere to bacterial cells and trigger Zn 2+ release in an acidic infectious microenvironment. ZPE NCs exhibit a significantly enhanced bactericidal effect compared to commercial zinc oxide nanoparticles (ZnO NPs) and dissociative Zn 2+ , achieving rapid eradication of both Gram‐positive Staphylococcus aureus (MRSA) and Gram‐negative Pseudomonas aeruginosa (P.a). Encapsulation of Zn 2+ in ZPE NCs effectively prevents its deactivation by proteins, so ZPE NCs maintain potent antibacterial activity even in protein‐rich environments. Additionally, ZPE NCs do not exhibit obvious cytotoxicity to NIH 3T3 cells even after 72 h incubation measured by CCK‐8 assay. The combination of high antibacterial efficiency and low cytotoxicity renders ZPE NCs a promising non‐antibiotic strategy for treating bacterial infections in the future.