X-ray-Triggered Self-Sustaining Afterglow Scaffolds with Persistent Type-I/II ROS Generation for Imaging-Guided Hypoxic Tumor Therapy

Afterglow imaging-guided photodynamic therapy (PDT) eliminates tissue autofluorescence and enables real-time therapeutic monitoring, yet its efficacy is constrained by shallow light penetration and tumor hypoxia. X-ray activation overcomes the depth barrier, but an integrated platform that simultaneously addresses hypoxia and provides persistent afterglow feedback remains lacking. Herein, we report a self-sustaining afterglow scaffold (TBR) constructed from a triphenylamine-derived sulfur-containing heterocycle bearing a p-dimethylaminophenylvinyl terminal group, featuring a donor−π–donor−π–acceptor (D−π–D−π–A) architecture around an aggregation-induced emission core. After nanoprecipitation with Pluronic F127, TBR nanoparticles (TBR-NPs) adopt a fluorescence-quenched state enabled by an ultrasmall singlet–triplet energy gap, thereby maximizing X-ray energy conversion to generate both oxygen-independent type-I (•OH, O2•–) and type-II (1O2) reactive oxygen species (ROS). Critically, the initially generated ROS undergo cycloaddition with TBR to form a cyclic peroxide intermediate; spontaneous dark decomposition releases stored chemical energy, re-exciting adjacent TBR molecules to sustain ROS production and generate near-infrared afterglow via a chemically initiated electron exchange luminescence (CIEEL) mechanism. This self-sustaining loop enables fractionated X-ray regimens that yield higher cumulative ROS than continuous exposure, while the type-I pathway ensures efficacy under hypoxia. A tumor-activatable derivative (BTBR) with H2O2-responsive boronate caging achieves high-contrast, tumor-specific afterglow imaging (signal-to-background ratio > 120) and enables hypoxic tumor ablation (95.8% inhibition) with real-time afterglow monitoring. By establishing a unified molecular platform that overcomes the dual barriers of penetration depth and hypoxia, this work provides a robust and generalizable strategy for advancing X-ray-triggered afterglow imaging-guided cancer therapy.