Charge-shielding assembly enables biointerface engineering of polyhexamethylene biguanide for selective and resistance-resilient antibacterial therapy

Cationic antimicrobial polymers are promising membrane-active antibacterial materials because they can rapidly kill bacteria and reduce the likelihood of resistance evolution. However, their strong membrane-disruptive activity often lacks sufficient bacterial-host selectivity, leading to substantial cytotoxicity and limiting their therapeutic applications. Here, we report a charge-shielding assembly strategy that uses dextran sulfate sodium to engineer the effective cationic charge density and biointerface behavior of polyhexamethylene biguanide (PHMB), a clinically used antimicrobial polymer. Dextran sulfate sodium (DSS), an anionic biopolymer, was used to form an electrostatic assembly with PHMB, termed PHMB@DSS. By tuning the PHMB:DSS mass ratio, a 2:1 formulation was identified as the optimal composition, which preserved strong and rapid bactericidal activity against clinically relevant drug-resistant pathogens while markedly reducing PHMB-induced membrane disruption and cytotoxicity toward mammalian cells. Mechanistic studies showed that DSS-mediated charge shielding modulated the surface charge presentation of PHMB, enabling PHMB@DSS to retain preferential interactions with anionic bacterial envelope components while substantially attenuating nonspecific disruption of mammalian cell membranes. The complex also entered mammalian cells mainly through energy-dependent endocytic pathways, consistent with its reduced direct membrane-damaging effect. PHMB@DSS maintained antibacterial performance in serum-containing medium, blood-associated infection assays, and bacteria-host cell co-culture models. In a methicillin-resistant Staphylococcus aureus intraperitoneal infection mouse model, PHMB@DSS exhibited improved tolerability and robust therapeutic efficacy comparable to vancomycin under the tested conditions. This work establishes charge-shielding assembly as a simple charge-density engineering strategy for improving the bacterial-host selectivity, biocompatibility, and anti-infective potential of cationic antimicrobial polymers.