Iodine-125-Labeled Graphdiyne Enables Photothermal-Enhanced Radiosensitization for Synergistic Therapy of Esophageal Cancer.

PURPOSE: Iodine-125 (125I) brachytherapy delivers continuous low-dose γ-irradiation for advanced esophageal cancer, but its efficacy is constrained by intrinsic tumor radioresistance and by the risk of normal-tissue injury arising from shedding of the radionuclide from the tumor site. This study aimed to develop a multifunctional nanoplatform coupling 125I delivery with photothermal-enhanced radiosensitization for synergistic therapy. METHODS: A polymeric peptide-functionalized graphdiyne (GDY) nanoplatform (GDY-PEG-PTyr) was constructed by conjugating an amphiphilic PEG-PTyr copolymer (prepared by ring-opening polymerization of tyrosine N-carboxyanhydride) onto GDY nanosheets, followed by 125I labeling via chloramine-T oxidation. The nanocomposite was characterized by TEM, XRD, Raman, XPS, FTIR, and thermogravimetric analysis, and its photothermal behavior was evaluated under 808 nm near-infrared (NIR) irradiation. Therapeutic efficacy and underlying mechanisms were assessed in KYSE-150 esophageal carcinoma cells and in tumor-bearing mice using cell viability, reactive oxygen species (ROS), γ-H2AX, live/dead, and histological assays. RESULTS: GDY-PEG-PTyr exhibited a two-dimensional sheet-like morphology, a high radiolabeling yield (~95%), and radiochemical stability above 80% over 72 h, and it reached mild hyperthermia (42-45 °C) with reproducible photothermal output over repeated heating-cooling cycles. In vitro, the combined GDY-PEG-PTyr-125I + NIR treatment reduced cell viability to 16.15%, far below that of either modality alone, while generating the strongest intracellular ROS signal, the most γ-H2AX foci, and pronounced upregulation of BAX and Caspase-3. In vivo, this combination produced near-complete tumor regression, with complete tumor elimination in three of five mice, and induced no detectable systemic toxicity. CONCLUSION: The GDY-PEG-PTyr-125I nanoplatform integrates radionuclide brachytherapy with photothermal therapy, in which localized hyperthermia amplifies radionuclide-induced oxidative stress and DNA double-strand breaks to drive apoptosis, offering a promising nanomedicine strategy for overcoming radioresistance in esophageal cancer.