Abstract The rise of antibiotic resistance, coupled with a dwindling antibiotic pipeline, presents a significant threat to public health. Consequently, there is an urgent need for novel therapeutics targeting antibiotic‐resistant pathogens. Nisin, a promising peptide antibiotic, exhibits potent bactericidal activity through a mechanism distinct from that of clinically used antibiotics. However, its cationic nature leads to hemolysis and cytotoxicity, which has limited its clinical application. Here, nanodelivery systems have been developed by mimicking the mechanisms bacteriophages use to deliver their genomes to host bacteria. These systems utilize bacteriophage receptor‐binding proteins conjugated to loading modules, enabling efficient targeting of bacterial pathogens. Peptide antibiotics are loaded via dynamic covalent bonds, allowing for infection microenvironment‐responsive payload release. These nanodelivery systems demonstrate remarkable specificity against target pathogens and effectively localize to bacteria‐infected lungs in vivo. Notably, they significantly reduce the acute toxicity of nisin, rendering it suitable for intravenous administration. Additionally, these bacteriophage‐mimicking nanomedicines exhibit excellent therapeutic efficacy in a mouse model of MRSA‐induced pneumonia. The facile synthesis, potent antimicrobial performance, and favorable biocompatibility of these nanomedicines highlight their potential as alternative therapeutics for combating antibiotic‐resistant pathogens. This study underscores the effectiveness of bacteriophage mimicry as a strategy for transforming peptide antibiotics into viable therapeutics.

Enhancing the Therapeutic Potential of Peptide Antibiotics Using Bacteriophage Mimicry Strategies