Phototriggered Biofilm Nanodisruptor with Genetic Modulation for Treating Drug-Resistant Bacterial Infections

Biofilm-associated bacterial infections pose significant therapeutic challenges due to their enhanced antibiotic resistance and complex extracellular matrix structure. To address this, we developed a carrier-free nanocomposite (named SPX-ICG) through self-assembling the antibiotic sparfloxacin (SPX) and the photosensitizer indocyanine green (ICG), creating a triple-mode antibacterial system that integrates photothermal, photodynamic, and antibiotic therapies. Upon near-infrared irradiation, SPX-ICG disassembled in the acidic biofilm environment, releasing bioactive components and initiating a therapeutic cascade: ICG generated mild photothermal effects that enhanced biofilm permeability, while simultaneously producing reactive oxygen species through photodynamic therapy, enabling efficient antibiotic penetration and bacterial eradication. The transcriptomic analysis revealed that SPX-ICG significantly downregulated genes involved in quorum sensing and two-component signal transduction systems, suggesting a fundamental reshaping of the biofilm microenvironment. Furthermore, SPX-ICG also demonstrated superior in vivo antibacterial effects in infected mouse models, effectively eradicating <i>Staphylococcus aureus</i> (<i>S. aureus</i>) and SPX-resistant <i>S. aureus</i> strains, with enhanced wound healing and minimal systemic toxicity. This approach, coupled with its minimalist design, presents a promising treatment option for the clinical management of biofilm-associated severe skin and soft tissue infections.