摘要Multidrug-resistant bacterial infections are increasing globally and posing a greater threat to human health.The application of direct bactericidal agents can induce secondary infections and treatment failures.The antibacterial strategy of the innate immune system brings inspiration.Here,we developed highly stable bacterial-aggregating peptides with immunoregulatory function.These peptides were designed to capture multidrug-resistant bacteria,prevent their dissemination,and activate the antibacterial immune response of the host.Among these peptides,the central-bola amphiphile R2F4R2 highly captured bacteria without directly killing them.R2F4R2 was believed to self-assemble through the lateral connection of peptide chains.The tetra-Phe segments formed a hydrophobic core of nanoparticle,with Arg residues appearing on the surface.Notably,R2F4R2 enhanced chemotactic response and phagocytic ability of macrophages,supported a transition to M2-macrophage phenotype to combat bacterial infection.Transcriptome sequencing and molecular docking analyses revealed that R2F4R2 regulated the gene expression associated with immunoregulatory functions and modulated calcium-Rap1 signaling pathways.Finally,R2F4R2 exhibited exceptional stability against proteolytic degradation and effectively entrapped invading pathogenic bacteria Escherichia coli to alleviate skin infections and intestinal inflammation.Overall,the bacterial-aggregating peptides represent a novel and effective strategy to combat multidrug-resistant infections.