Synergistic Antibacteria and Anti‐Inflammation with Reversible Redox Selenium‐Functionalized Polypeptides for Efficient Gram‐Negative Bacterial Sepsis Treatment

Abstract Gram‐negative sepsis, a leading cause of intensive care unit mortality, is exacerbated by dysregulated host inflammation and escalating antimicrobial resistance. The release of lipopolysaccharide (LPS) following antibiotic treatment and the resulting proinflammatory cascade necessitate the simultaneous application of effective inflammation management. Herein, a series of selenium‐functionalized polypeptides are developed with the reversible redox properties of selenium and positive charge units, having negative antibacterial and anti‐inflammatory synchronously. The optimal peptide, PSe 50 ‐CF, can effectively kill many Gram‐negative bacteria, including E. coli , P. aeruginosa , and A. baumannii belonging to the ESCAPE family. PSe 50 ‐CF disrupts outer membrane integrity and inhibits LPS biosynthesis via dual targeting of LPS and phospholipids and further downregulates critical genes for lipid A biosynthesis and the BamA component of the β‐barrel assembly machinery (BAM complex). Crucially, leveraging selenium's reversible redox and immune regulation properties, PSe 50 ‐CF exhibited potent anti‐inflammatory effects both in vitro and in vivo by neutralizing LPS and suppressing Toll‐like receptor 4 (TLR4) signaling, thereby blocking proinflammatory cytokines. This dual‐action mechanism translates to superior therapeutic efficacy in murine models of cecal ligation/puncture (CLP) sepsis and E. coli ‐induced peritonitis. Together, these findings position selenium‐functionalized polypeptides as a highly promising therapeutic strategy for Gram‐negative sepsis therapy and a paradigm for next‐generation antimicrobial design.