Structurally Engineered SO₂-Releasing Polymeric Nanoassembly for Broad-Spectrum Antibacterial Activity

Cationic antimicrobial agents are widely recognized for combating microbial infections through their membrane-disruptive properties. Recently, sulfur dioxide (SO₂) gas therapy has emerged as a promising alternative for treating diseases, including bacterial infections. However, current systems often target only specific bacterial strains. Herein, we present amphiphilic alternating copolymers, DAP (x = 1, 2, 3), incorporating cationic residues and thiol-responsive SO₂-releasing moieties. In aqueous environments, DAP copolymers self-assemble into micellar nanoassemblies (DAP), exposing hydrophilic cationic residues outward and encapsulating hydrophobic SO₂-releasing moieties within the core to enable controlled and sustained release of SO₂ in the presence of glutathione (GSH). In vitro studies reveal excellent biocompatibility of DAP2 Np with broad-spectrum antibacterial activity against both Gram-positive (Bacillus subtilis, Staphylococcus aureus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria. Mechanistic investigations confirm bacterial eradication via membrane disruption and reactive oxygen species generation. This study underscores the remarkable efficacy of SO₂-releasing cationic polymers in resisting bacterial infections.