Membrane-selective antimicrobial polysaccharides: Homogeneous synthesis of guanidinylated chitosan for simultaneous...

Antimicrobial resistance is an escalating global health threat that demands therapeutic strategies beyond conventional antibiotics. Natural polysaccharides provide attractive scaffolds for multifunctional antimicrobial materials; however, selective bacterial targeting with preserved biocompatibility remains difficult to achieve. Here, we report a homogeneous aqueous strategy for synthesizing guanidinylated chitosan (GCS) with tunable degrees of substitution (DS). The optimized derivative, GCS-2 (DS = 0.17), self-assembled into spherical nanostructures (28.6 ± 4.4 nm) with a positive ζ-potential (32.1 ± 2.7 mV), enabling strong electrostatic interactions with bacterial membranes. GCS-2 showed potent activity against the marine pathogen Vibrio vulnificus, with a minimum inhibitory concentration of 25 μg/mL, and killed bacteria through membrane-selective disruption. In addition to direct antimicrobial activity, GCS-2 supported wound repair by promoting neovascularization, myofibroblast activation, collagen remodeling, and re-epithelialization without exacerbating inflammation. This dual-function polysaccharide platform integrates pathogen elimination with tissue-regenerative support and provides a promising strategy for treating complex infected wounds.