Engineering a Hydrogen Peroxide-Activated Hydrogen Sulfide Donor-Based Fluorescent Agent for Integrated Diagnosis and Therapy of Chronic Wounds

Diabetic chronic wounds are one of the most severe complications of diabetes mellitus, which are pathologically characterized by persistent oxidative stress-inflammatory cascades. Thus, it is vital for effective diagnosis and treatment of diabetic chronic wounds by targeting the critical pathological oxidative stress feature in the tissue microenvironment. Herein, regarding the overexpressed hydrogen peroxide (H₂O₂) at the oxidative stress sites, we innovatively developed a H₂O₂-activated hydrogen sulfide (H₂S) donor-based near-infrared fluorescent theragnostic agent (<b>NDTA</b>) to achieve synergistic therapy of diabetic chronic wounds through dynamic visualization of H₂O₂ gradients and targeted H₂S delivery. The <b>NDTA</b> system employs pentafluoro benzenesulfonate as an H₂O₂-specific responsive unit, enabling dual functions via an electron rearrangement-triggered molecular switching: (1) H₂O₂ monitoring: real-time characterization of H₂O₂ concentration at wound sites, reflected by intensity changes of 719 nm near-infrared emission; (2) On-demand H₂S release: activation of a self-immolative cascade to precisely deliver thiocarbamate prodrugs, which are enzymatically converted by wound tissue carbonic anhydrase into endogenous H₂S. The results of tissue sequencing analysis demonstrate that the molecular mechanism by which H₂S promotes wound repair is predominantly associated with its regulatory modulation of the tumor necrosis factor (TNF) signaling pathway. This technology overcomes the limitations of conventional diagnostic-therapeutic separation by integrating H₂O₂-guided fluorescence imaging with spatiotemporally controlled H₂S release, offering a microenvironment-adaptive theragnostic platform for precision medicine in diabetic wound management.