Glycan-decorated polymeric nanomedicine for the treatment of multidrug-resistant infections

Abstract

The antimicrobial resistance (AMR) crisis necessitates strategies to revitalize existing antibiotics against multidrug-resistant pathogens. While cationic antimicrobial polymers can disrupt bacterial membranes, their clinical translation is hindered by host toxicity. Here we report a hierarchical, stimuli-responsive nanomedicine designed on principles of safety, specificity, switchability, and synergy. We synthesized phenylboronic ester-caged biodegradable polymers shielded by functional polysaccharide shells. These nanoparticles remain inert during circulation but selectively activate within infection microenvironments. Upon activation, the exposed cationic polymer physically compromises bacterial membranes, enabling the entry of co-delivered antibiotics such as rifampicin into Gram-positive, Gram-negative, mycobacterial, and biofilm-embedded pathogens. Our research led to the discovery of glycans that significantly improve therapeutic outcomes. We found that different glycans exhibited distinct effects in various tissues and conditions: chondroitin sulfate effectively targeted CD44-abundant infectious niches, enabling precise localization and enhanced therapeutic efficacy, whereas levan uniquely stimulated macrophage oxidative bursts, promoting intracellular pathogen clearance. By leveraging these distinct biological interactions, our platform overcomes the physical and biological barriers of AMR, offering a universal strategy to treat diverse, multidrug-resistant infections.