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

Abstract 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).