Designing Self‐Assembling Chimeric Peptide Nanoparticles with High Stability for Combating Piglet Bacterial Infections

Abstract As a novel type of antibiotic alternative, peptide‐based antibacterial drug shows potential application prospects attributable to their unique mechanism for lysing the membrane of pathogenic bacteria. However, peptide‐based antibacterial drugs suffer from a series of problems, most notably their immature stability, which seriously hinders their application. In this study, self‐assembling chimeric peptide nanoparticles (which offer excellent stability in the presence of proteases and salts) are constructed and applied to the treatment of bacterial infections. In vitro studies are used to demonstrate that peptide nanoparticles NPs1 and NPs2 offer broad‐spectrum antibacterial activity and desirable biocompatibility, and they retain their antibacterial ability in physiological salt environments. Peptide nanoparticles NPs1 and NPs2 can resist degradation under high concentrations of proteases. In vivo studies illustrate that the toxicity caused by peptide nanoparticles NPs1 and NPs2 is negligible, and these nanoparticles can alleviate systemic bacterial infections in mice and piglets. The membrane permeation mechanism and interference with the cell cycle differ from that of antibiotics and mean that the nanoparticles are at a lower risk of inducing drug resistance. Collectively, these advances may accelerate the development of peptide‐based antibacterial nanomaterials and can be applied to the construction of supramolecular nanomaterials.