Hydrogen‐Bonded Organic Framework Nanoscintillators for X‐Ray‐Induced Photodynamic Therapy in Hepatocellular Carcinoma

X-ray induced photodynamic therapy (X-PDT) leverages penetrating X-ray to generate singlet oxygen (¹O₂) for treating deep-seated tumors. However, conventional X-PDT typically relies on heavy metal inorganic scintillators and organic photosensitizers to produce ¹O₂, which presents challenges related to toxicity and energy conversion efficiency. In this study, highly biocompatible organic phosphorescent nanoscintillators based on hydrogen-bonded organic frameworks (HOF) are designed and engineered, termed BPT-HOF@PEG, to enhance X-PDT in hepatocellular carcinoma (HCC) treatment. BPT-HOF@PEG functions simultaneously as both scintillator and photosensitizer, effectively absorbing and transferring X-ray energy to generate abundant ¹O₂. Both in vitro and in vivo investigations demonstrate that internalized BPT-HOF@PEG efficiently produces significant quantities of ¹O₂ upon X-ray irradiation. Additionally, X-ray exposure directly inflicts DNA damage, and the synergistic effects of these mechanisms result in pronounced cell death and substantial tumor growth inhibition, with a significant inhibition rate of up to 90.4% in vivo assessments. RNA sequencing analyses reveal that X-PDT induces apoptosis in Hepa1-6 cells while inhibiting cell proliferation, culminating in tumor cell death. Therefore, this work highlights the considerable potential of efficient phosphorescent HOF nanoscintillators-based X-PDT as a promising therapeutic approach for HCC, providing a highly effective alternative with negligible toxicity for patients with unresectable tumors.