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 (O) for treating deep-seated tumors. However, conventional X-PDT typically relies on heavy metal inorganic scintillators and organic photosensitizers to produce O, 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 O. Both in vitro and in vivo investigations demonstrate that internalized BPT-HOF@PEG efficiently produces significant quantities of O 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.