Specific Clearance of Lipopolysaccharide from Blood Based on Peptide Bottlebrush Polymer for Sepsis Therapy

Abstract Lipopolysaccharide (LPS) is the primary bacterial toxin that is vital to the pathogenesis and progression of sepsis associated with extremely high morbidity and mortality worldwide. However, specific clearance of LPS from circulating blood is highly challenging because of the structural complexity and its variation between/within bacterial species. Herein, a robust strategy based on phage display screening and hemocompatible peptide bottlebrush polymer design for specific clearance of targeted LPS from circulating blood is proposed. Using LPS extracted from Escherichia coli as an example, a novel peptide (HWKAVNWLKPWT) with high affinity (K_D < 1.0 nм), specificity, and neutralization activity (95.9 ± 0.1%) against the targeted LPS is discovered via iterative affinity selection coupled with endotoxin detoxification screening. A hemocompatible bottlebrush polymer bearing the short peptide [poly(PEGMEA‐co‐PEP‐1)] exhibits high LPS selectivity to reduce circulating LPS level from 2.63 ± 0.01 to 0.78 ± 0.05 EU mL⁻¹ in sepsis rabbits via extracorporeal hemoperfusion (LPS clearance ratio > 70%), reversing the LPS‐induced leukocytopenia and multiple organ damages significantly. This work provides a universal paradigm for developing a highly selective hemoadsorbent library fully covering the LPS family, which is promising to create a new era of precision medicine in sepsis therapy.