Tumor in-situ self-assembling gold nanorods for photothermally enhanced radiotherapy enabled by multilevel radiosensitization mechanisms

Radiotherapy is one of the principal modalities for cancer treatment. However, its efficacy is often limited by a complex interplay of various factors, including high level antioxidant in tumor cells, efficient DNA damage repair capabilities, serious tumor tissue fibrosis and consequent hypoxia, etc. Hence, it represents a critical challenge for enhancing radiotherapy efficacy and reducing side effects to develop a radiosensitizer that can specifically work to the tumor while simultaneously incorporating multiple sensitization effects. Herein, a tumor in situ self-assembling gold nanorods (GNRs) system is developed to specifically form aggregates within tumor cells, resulting in a photothermal-enhanced radiotherapy via multilevel radiosensitization mechanisms. At the molecular level, the GNRs nanoagents suppress the transcription of radioresistance-associated genes under the control of the TGF-β signaling pathway by inhibiting TGF-β/Smad2/3 activation. Simultaneously, by downregulating key DNA repair proteins, the nanoagents compromise the ability of tumor cells to repair DNA damage induced by radiation. At the cellular level, the GNRs nanoagents induce cell cycle arrest at the G2/M phase, thereby sensitizing tumor cells to radiative energy. At the tissue level, under photothermal-enhanced ionizing radiation, the GNRs nanoagents reduce the activation of cancer-associated fibroblasts and facilitate the degradation of major extracellular matrix (ECM) components including collagen I and fibronectin. The remodeling of the ECM alleviates the hypoxic tumor microenvironment and, consequently, overcomes the associated radiotherapy resistance. This work reports a multifunctional radiosensitization platforms with systemic and multilevel synergistic mechanisms, providing an attractive paradigm for efficient cancer radiotherapy and facilitating combination therapy. STATEMENT OF SIGNIFICANCE: Radiotherapy is one of the principal modalities for cancer treatment, but its efficacy is often hindered by a protective "cell-microenvironment alliance." This network involves tumor antioxidant molecules, efficient DNA repair, a fibrotic and hypoxic tumor microenvironment (TME). Existing studies largely target tumor cells or the TME separately, neglecting their interaction and combined modulation. In this study, we developed a tumor in situ self-assembling gold nanorods system that employed a synergistic modulation strategy to simultaneously enhance the intrinsic radiosensitivity of tumor cells and modulate the radioresistant microenvironment, thereby achieving complementary mechanisms to improve radiotherapy efficacy. This system offers a comprehensive, clinically translatable strategy for a new generation of intelligent, multifunctional radiosensitization platforms.