ZIF-8-Based Dual-Modal Smart Responsive Nanoplatform for Overcoming Radiotherapy Resistance in Advanced Tumors

Radiation therapy is one of the core means of tumor treatment, especially in local control and radical treatment has an irreplaceable role. However, radiotherapy resistance is one of the major challenges in current clinical practice. Tumor cells have a strong ability to repair DNA damage, which can effectively resist DNA double-strand breaks caused by X-ray, thus weakening the killing effect of radiotherapy. In addition, the complexity of the tumor microenvironment (TME) will further reduce the sensitivity of radiotherapy, leading to poor treatment results. With the rapid development of nanotechnology, multi-modal combined therapy nanoplatform has gradually become a new strategy to overcome radiotherapy resistance. These nanoplatforms achieve synergies by integrating multiple therapeutic approaches, such as radiation sensitization, photothermal therapy and chemotherapy. In this study, we utilized ZIF-8, a member of the metal-organic frameworks, to simultaneously load ICG and Rapamycin for X-ray sensitization and combined photothermal therapy. In this formulation, Rapamycin enhances tumor cells' sensitivity to radiotherapy by inhibiting the mTOR signaling pathway, increasing DNA damage, regulating the cell cycle, and stimulating the STING pathway, which amplifies the tumor immune response. Meanwhile, ICG, as a photosensitizer, effectively converts light energy into heat, achieving tumor photothermal ablation. The modified drug-delivery system becomes a tumor-microenvironment-responsive smart carrier, increasing tumor cell uptake, prolonging retention at the tumor site, and achieving targeted drug delivery. It releases drugs in the specific tumor microenvironment, enhancing photothermal and radiotherapy sensitization effects. The results show that the smart dual-loaded nanoplatform effectively combines photothermal therapy and external-beam sensitization, reshapes the immunosuppressive tumor microenvironment and significantly inhibits tumor proliferation in the HepG2 subcutaneous xenograft model, demonstrating marked antitumor activity and good biosafety.