Deep Red-Light-Mediated Nitric Oxide and Photodynamic Synergistic Antibacterial Therapy for the Treatment of Drug-Resistant Bacterial Infections

Infections caused by persistent, drug-resistant bacteria pose significant challenges in inflammation treatment, often leading to severe morbidity and mortality. Herein, the photosensitizer rhodamine derivatives are selected as the light-trapping dye and the electron-rich substituent N-nitrosoaminophen as the nitric oxide (NO)-releasing component to develop a multifunctional (deep) red-light activatable NO photocage/photodynamic prodrug for efficient treatment of wounds and diabetic foot infections. The prodrug, RhB-NO-2 integrates antimicrobial photodynamic therapy (aPDT), NO sterilization, and NO-mediated anti-inflammatory properties within a small organic molecule and is capable of releasing NO and generating Reactive oxygen species (ROS) when exposed to (deep) red laser (660 nm). This strategy overcomes the limitation of using a single photosensitizer, which is often inadequate for eliminating drug-resistant bacteria. Additionally, it demonstrates that NO released from the prodrug can interact with superoxide anions (O₂ ^•-) generated by PDT to form a more reactive and oxidative agent, peroxynitrite (ONOO^-). These three components act synergistically to enhance the antimicrobial effects. Furthermore, the released NO can inhibit the NF-κB pathway by regulating the expression of toll-like receptor 2 (TRL2) and tumor necrosis factor-α (TNF-α), thereby alleviating tissue inflammation. The developed prodrug ， RhB-NO-2 has the potential to expedite the healing of superficial infected wounds and offer a promising approach for treating diabetic foot ulcers (DFUs).