Engineering Antimicrobial Metal–Phenolic Network Nanoparticles with High Biocompatibility for Wound Healing

Antibiotic‐resistant bacteria pose a global health threat by causing persistent and recurrent microbial infections. To address this issue, antimicrobial nanoparticles (NPs) with low drug resistance but potent bactericidal effects have been developed. However, many of the developed NPs display poor biosafety and their synthesis often involves complex procedures and the antimicrobial modes of action are unclear. Herein, a simple strategy is reported for designing antimicrobial metal‒phenolic network (am‐MPN) NPs through the one‐step assembly of a seeding agent (diethyldithiocarbamate), natural polyphenols, and metal ions (e.g., Cu2+) in aqueous solution. The Cu2+‐based am‐MPN NPs display lower Cu2+ antimicrobial concentrations (by 10–1000 times) lower than most reported nanomaterials and negligible toxicity across various models, including, cells, blood, zebrafish, and mice. Multiple antimicrobial modes of the NPs have been identified, including bacterial wall disruption, reactive oxygen species production, and quinoprotein formation, with the latter being a distinct pathway identified for the antimicrobial activity of the polyphenol‐based am‐MPN NPs. The NPs exhibit excellent performance against multidrug‐resistant bacteria (e.g., methicillin‐resistant Staphylococcus aureus (MRSA)), efficiently inhibit and destroy bacterial biofilms, and promote the healing of MRSA‐infected skin wounds. This study provides insights on the antimicrobial properties of metal‒phenolic materials and the rational design of antimicrobial metal‒organic materials. Antimicrobial, highly biocompatible metal‐phenolic network nanoparticles (am‐MPN NPs) are engineered and applied across different models (cells, blood, zebrafish, and mice). The NPs perform efficiently against multidrug‐resistant bacteria owing to their antimicrobial properties, which are related to 1) cell wall damage, 2) reactive oxygen species (ROS), and 3) quinoprotein production. Moreover, they inhibit and eradicate bacterial biofilms and promote the healing of bacterial‐infected skin wounds.