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, <b>DAP<i>x</i></b> (<i>x</i> = 1, 2, 3), incorporating cationic residues and thiol-responsive SO₂-releasing moieties. In aqueous environments, <b>DAP<i>x</i></b> copolymers self-assemble into micellar nanoassemblies (<b>DAP<i>x</i>Np</b>), 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 <b>DAP2 Np</b> with broad-spectrum antibacterial activity against both Gram-positive (<i>Bacillus subtilis</i>, <i>Staphylococcus aureus</i>) and Gram-negative (<i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>) 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.