Enhancing radiosensitization in triple-negative breast cancer by aptamer-modified nanoclusters NC-T5-5TR1

Radiotherapy is an important part of standard treatment for triple-negative breast cancer (TNBC); however, radioresistance significantly limits therapeutic outcomes. In this study, we developed a novel radiosensitizer based on aptamer-modified silver nanoclusters, NC-T5-5TR1, to potentiate radiotherapy efficacy against TNBC. NC-T5-5TR1 enabled real-time tumor imaging and accurate localization via their intrinsic fluorescence and targeting capability. When combined with ionizing radiation (IR), NC-T5-5TR1 significantly enhanced radiosensitization in vitro, as evidenced by decreased proliferation, increased apoptosis and higher reactive oxygen species (ROS) levels, and also markedly inhibited tumor growth in vivo. Transcriptomic analysis indicated that the IL-6/JAK2/STAT3 signaling pathway was downregulated under NC-T5-5TR1 + IR treatment, which was subsequently validated in vitro and in vivo. Rescue experiments confirmed that IL-6 overexpression reversed NC-T5-5TR1 combined with IR-induced JAK2/STAT3 inhibition and its downstream effects on proliferation, apoptosis, and ROS accumulation. Collectively, our findings demonstrated that NC-T5-5TR1 enhanced the radiosensitivity of TNBC cells, and this effect was associated with the modulation of the IL-6/JAK2/STAT3 axis, offering a promising strategy for improving the therapeutic efficacy of radiotherapy in TNBC.