Unique Dual‐Affinity Strategy for Specific Lipopolysaccharide Clearance in Sepsis Therapy: Peptide‐Conjugated Molecularly Imprinted Polymers via Emulsion Interfacial Polymerization

Abstract Sepsis is an infection‐induced organ dysfunction with high global morbidity and mortality. Specific clearance of lipopolysaccharides (LPSs), key pathological drivers in sepsis, from the bloodstream is critical for effective therapy. However, selective capture of LPS is challenging due to their structural heterogeneity, extremely low concentrations (ng·mL −1 ), and complexity of blood components. Here, a novel dual‐affinity strategy is presented for designing high‐specificity LPS adsorbents. Leveraging phage display, a high‐affinity peptide ligand (P‐HK) targeting the LPS family is identified by screening against their conserved Kdo 2 ‐Lipid A structure. Concurrently, delicate molecularly imprinted polymers (PS@PA+) with geometrically matched cavities are synthesized via emulsion interfacial polymerization, exploiting the oriented assembly of amphiphilic LPS templates at oil‐water interfaces. Conjugation of the imprinted polymers with the peptide ligand produced PS@PA‐P HK +, which exhibits highly specific LPS binding and demonstrates exceptional performance, including remarkable E. coli LPS clearance efficiency (99.2% in buffer; 95.4% in blood), high adsorption capacity (543 EU·mg −1 ), broad‐spectrum clearance of diverse bacterial LPSs, robust anti‐fouling properties, and satisfactory biocompatibility. Furthermore, PS@PA‐P HK +‐based hemoperfusion in a septic rabbit model confirmed significant therapeutic efficacy, remarkably reducing circulating LPS levels and mitigating organ damage. This material design overcomes the challenge of specific LPS clearance, offering substantial promise for transformative sepsis therapy.