Dual-functional self-assembled nanosystems with enhanced protease resistance: Promoting bacterial aggregation and immune activation for multidrug-resistant bacterial infection

Abstract

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.