pH‐Triggered Size‐Transformable and Bioactivity‐Switchable Self‐Assembling Chimeric Peptide Nanoassemblies for Combating Drug‐Resistant Bacteria and Biofilms

Abstract Drug‐resistant bacteria and biofilm‐associated infections are prominent problems in the field of antibacterial medicine, seriously affecting human and animal health. Despite the great potential of nanomaterials in the antibacterial field, overcoming the paradox of size and charge, efficient penetration, and retention within biofilms remain a formidable challenge. Here, self‐assembling chimeric peptide nanoassemblies composed of multiple functional fragments are designed for the treatment of drug‐resistant bacteria and biofilm‐associated infections. Notably, the chimeric peptide self‐assembles into nanofibers at pH 7.4 and is transformable into nanoparticles in the acidic biofilm‐infected microenvironment at pH 5.0, and thus achieves a size reduction and charge increase, improving the penetration into the bacterial biofilms and killing drug‐resistant bacteria by a mechanism dominated by membrane cleavage. In vivo mouse and piglet infection models confirm the ability of chimeric peptide nanoassemblies to reduce bacterial load within biofilms. Collectively, this research on pathological‐environment‐driven nanostructural transformations may provide a theoretical basis for designing high‐performance antibacterial nanomaterials and advance the application of peptide‐based nanomaterials in medicine and animal husbandry.