Disarming bacterial iron homeostasis and sulfur antioxidant defenses via coordination-driven photosensitizer de-aggregation for enhanced photodynamic infection eradication.

Abstract

Antibacterial photodynamic therapy (PDT) offers a resistance-proof strategy for bacterial elimination via reactive oxygen species (ROS). However, its efficacy is hindered by intrinsic bacterial oxidative stress tolerance. Furthermore, clinically relevant photosensitizers such as chlorin e6 (Ce6) suffer from aggregation-caused quenching due to π-π stacking in aqueous environments, limiting the applicability of PDT. Here, we constructed a coordination-engineered nanoconjugate by introducing Ga³⁺ to Ce6 in aqueous solution, which disrupts the ordered π-π stacking of Ce6, de-aggregates the aggregates into amorphous supramolecular assemblies, and simultaneously enhances their photoreactivity under physiological conditions. Multi-omics analyses demonstrated that GaCe6 induces potent extracellular ROS production and intracellular redox collapse by hijacking the Fur-regulated iron-sensing system and disrupting sulfur metabolism-marked by suppressed cysteine, bacillithiol and hydrogen sulfide biosynthesis. In addition, GaCe6 exhibited potent antibacterial, antibiofilm, and anti-persister activities, eradicating planktonic bacteria, mature biofilms, and drug-tolerant persister bacteria. In a murine S. aureus-infected wound model, GaCe6-mediated PDT achieved rapid bacterial clearance while reprogramming the immune microenvironment to promote angiogenesis and tissue regeneration. This work presents a structural ligand-enhanced PDT strategy that couples chemical coordination with metabolic interference, offering a potential clinical strategy for next-generation drug-resistant antibacterial therapies.