Cationic Antimicrobial Copolymers Reveal Immunomodulatory Properties in Lipopolysaccharide Stimulated Macrophages in Vitro

Antimicrobial polymers, which have emerged as a promising alternative to antibiotics in the fight against antimicrobial resistance, are based on the design of cationic host defense peptides (CHDPs). Being part of the mammalian innate immune system, CHDPs possess both antimicrobial and immunoregulatory effects to manage bacterial infections. However, the immunomodulatory effects of antimicrobial polymers remain largely unexplored. Within this work, a library of 15 copolymers was synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization and their abilities to modulate pro-inflammatory pathways in lipopolysaccharide (LPS)-activated murine and human macrophages were investigated. We found that two diblock copolymers with cationic units copolymerized with either apolar or hydrophilic comonomers appeared to have anti-inflammatory activity through suppression of the activation of the nuclear factor kappa-light-chain enhancer of the activated B cell (NF-κB) signaling pathway, scavenging of reactive oxygen species, and reduced production of the pro-inflammatory cytokine interleukin-6 (IL-6). Furthermore, the cationic-apolar copolymer exhibits significant antimicrobial activity against P. aeruginosa. Thus, this promising copolymer holds potential as a dual-action therapeutic, effectively combating bacterial infections while curbing prolonged inflammation and thereby preventing sepsis at the site of infection.