Proteolytic-Resistant Self-Assembling Peptide Nanofibers Combat Specific Bacterial Infections via Trap-and-Kill

The rise in global antibiotic resistance highlights the urgent need for effective antimicrobial agents. Antimicrobial peptides (AMPs) offer a potential solution to combat bacterial resistance. However, key challenges remain in addressing the limitations of current peptide drugs and biomaterials, such as narrow action modes, poor protease stability, and challenges in pathogen-specific targeting. This study introduces a series of multifunctional AMPs by integrating self-assembling systems. By regulating the length of cationic amino acid side chains, the optimized peptide Nhar was identified as a triple-functional candidate with the potential to solve these limitations. In aqueous solutions, Nhar self-assembles into nanofibers that trap pathogens, prevent their spread, and selectively kill Gram-positive bacteria. Nhar demonstrates remarkable protease resistance, retaining antimicrobial activity even under 10 mg/mL protease conditions. It induces bacterial death primarily through membrane disruption and multiple synergistic mechanisms. In a Staphylococcus aureus induced mouse bacteremia model, Nhar showed promising therapeutic potential. This work offer important insights for developing multifunctional antimicrobial therapies.