X‐Ray‐Activated ROS Storm: A Multimechanistic SAO25‐AO@Gel Platform for Deep‐Tissue Bacterial Eradication

Abstract The rise of antibiotic resistance and limited tissue penetration of conventional antibacterial photodynamic therapy (aPDT) necessitate innovative solutions for deep‐seated infections. Here, an X‐ray‐activated, multimechanistic gel platform is reported that, for the first time to synergizes radiodynamic therapy (RDT), X‐ray‐excited photodynamic therapy (X‐PDT), and post‐irradiation PDT to induce a sustained reactive oxygen species (ROS) storm for deep‐tissue bacterial eradication. The system integrates strontium aluminate phosphors (SAO25), which exhibit both X‐ray‐induced radiodynamic activity and persistent luminescence (PersL), with the radio/photosensitizer acridine orange (AO) in a biocompatible gel matrix. This design enables three complementary ROS generation pathways: SAO25's intrinsic radiodynamic activity, AO's intrinsic radiodynamic effects, and energy transfer‐mediated photodynamic activation of AO during and post X‐ray irradiation. This multi‐mechanistic approach yields diverse ROS ( 1 O 2 , •O 2 − , •OH, H 2 O 2 ) with extended activity, achieving ≈99% bactericidal efficacy against both Gram‐positive ( S. aureus ) and Gram‐negative ( E. coli ) pathogens in vitro, ≈90% biofilm disruption, and potent antibacterial effect through 1.5 cm of tissue in a pork model. In vivo studies demonstrate dual‐mode fluorescence/PersL imaging guidance, and 95.4% recovery in a deep abscess model. The platform's biocompatibility, adaptability, and resistance mitigation potential establish a promising paradigm for treating recalcitrant deep‐seated infections.