LPS‐Binding Hydrogel for TLR4‐Mediated Microbiota‐Immune Modulation

Abstract

Abstract Lipopolysaccharide (LPS), a conserved component of Gram‐negative bacteria, is a potent immune activator that disrupts tissue repair when released during microbial dysbiosis. LPS‐scavenging strategies are often limited by the poor accessibility of lipid A, the bioactive core of LPS, which is shielded by variable oligosaccharide structures and embedded in bacterial membranes. To address this, a synergistic LPS‐binding hydrogel (OCMC‐PMBP) is developed, combining polymyxin B (PMB) for lipid A‐targeted bacterial lysis and polyethyleneimine (PEI) for electrostatic LPS capture. This system is applied to oronasal‐perforating wounds, a complex and infection‐prone condition associated with cleft palate repair. Clinical microbiome analysis and murine models reveal that LPS‐TLR4 signaling contributes to immune dysregulation and impaired healing. OCMC‐PMBP treatment reduces LPS levels, restores microbiota balance, suppresses inflammation, and accelerates epithelial regeneration and collagen remodeling. Integrated 16S rRNA sequencing, metagenomics, and single‐cell transcriptomics show that the hydrogel reprograms immune cell phenotypes and modulates macrophage interactions with neutrophils, epithelial cells, and fibroblasts across healing phases. This study introduces a biomaterials design combining antimicrobial and immunomodulatory functions to resolve dysbiosis‐induced inflammation and enhance regenerative healing in complex mucosal wounds.