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The robust outer membrane barrier (OM) is the main factor contributing to the antibiotic resistance of multidrug-resistant Gram-negative bacteria (MDR GNB). Breaking this barrier is a powerful strategy to overcome this challenge. This paper proposes a carbon monoxide (CO)-driven cascade inhibition strategy aimed at disrupting the OM barrier, with the aim of significantly enhancing the antibacterial efficacy of existing treatments. As a proof of concept, we developed AIE&CO@G3 nanogels, which combine CO-releasing molecules (CORM-401) and aggregation-induced emission (AIE) photosensitizers (PSs). CO significantly enhanced the antibacterial photodynamic therapy (AIE-aPDT) based on AIE PSs, and similar synergistic effects were observed when combined with multiple first-line antibiotics. Mechanistically, CO-induced OM disruption promoted the penetration of AIE PS and antibiotics, thereby significantly improving their efficacy in vitro (for various MDR GNB) and in vivo (in MDR P. aeruginosa bacterial keratitis and pneumonia models). This goal was achieved by inhibiting ATP synthesis and disrupting the biosynthesis and transport of glycerophospholipids (GPL) and lipopolysaccharides (LPS). This pioneering study highlights the potential of carbon monoxide in OM disruption and provides a new strategy for combating MDR GNB infections. This study was published in Biomaterials under the title "CO-driven cascade disruption of the outer membrane barrier: A potent strategy to enhance the treatment of gram-negative bacterial infections".
Reference News: DOI: 10.1016/j.biomaterials.2026.124214
