White light-triggered cascade NO/ROS-releasing platform with synergistic antibacterial and angiogenic effects for infected wound healing.

Abstract

Effective treatment of infected wounds requires concurrent control of microbes and restoration of vascular supply. Conventional therapies, including antibiotics and growth factors, suffer from limited efficacy and stability. Nitric oxide (NO) and reactive oxygen species (ROS) are promising alternatives that can eliminate bacteria and promote tissue regeneration. However, most current delivery systems use separate donors with simultaneous release, making control difficult and risking harmful peroxynitrite formation. Here, we report TPPF-NO, an organic small molecule based cascade NO/ROS donating platform activated by low-power white light (5 mW cm^-2). Upon irradiation, TPPF-NO rapidly liberates NO, then converts into a photosensitizer (TPPF) that produces ROS in a controllable manner. Spectroscopy, Griess reaction analysis and electron paramagnetic resonance confirm the fast NO release and lightdriven ROS generation. Under mild illumination, TPPF-NO disrupt biofilms, enhance cell migration, and stimulate endothelial tube formation. Transcriptomic and validation studies confirm activation of IGF1-PI3K-AKT signaling and suppression of FoxO pathway. In infected mouse model, topical TPPF-NO with white light activation accelerates wound closure, reduces inflammation, and promotes neovascularization with favorable systemic safety. This controllable cascade NO/ROS releasing platform offers a promising and practical strategy for infected wound therapy and other situations requiring coordinated NO and ROS signaling. STATEMENT OF SIGNIFICANCE: Effective treatment of infected wounds remains a major clinical challenge due to bacterial resistance and delayed tissue regeneration. This study introduces TPPF-NO, a light-responsive molecule that releases nitric oxide (NO) and reactive oxygen species (ROS) in a temporally separated manner. This cascade strategy enhances antibacterial efficacy while minimizing oxidative damage. Beyond disinfection, TPPF-NO promotes vascularized tissue regeneration by modulating immune response and activating the FOXO signaling pathway. These findings provide a novel paradigm for designing multifunctional wound therapies that couple infection control with tissue repair, offering broad relevance in biomaterials, phototherapy, and regenerative medicine.