A NIR‐II AIEgen‐Based Supramolecular Nanodot for Peroxynitrite‐Potentiated Mild‐Temperature Photothermal Therapy of Hepatocellular Carcinoma

Abstract Compared to conventional photothermal therapy (PTT) which requires hyperthermia higher than 50 °C, mild‐temperature PTT is a more promising antitumor strategy with much lower phototoxicity to neighboring normal tissues. However, the therapeutic efficacy of mild‐temperature PTT is always restricted by the thermoresistance of cancer cells. To address this issue, a supramolecular drug nanocarrier is fabricated to co‐deliver nitric oxide (NO) and photothermal agent DCTBT with NIR‐II aggregation‐induced emission (AIE) characteristic for mild‐temperature PTT. NO can be effectively released from the nanocarriers in intracellular reductive environment and DCTBT is capable of simultaneously producing reactive oxygen species (ROS) and hyperthermia upon 808 nm laser irradiation. The generated ROS can further react with NO to produce peroxynitrite (ONOOˉ) bearing strong oxidization and nitration capability. ONOOˉ can inhibit the expression of heat shock proteins (HSP) to reduce the thermoresistance of cancer cells, which is necessary to achieve excellent therapeutic efficacy of DCTBT‐based PTT at mild temperature (<50 °C). The antitumor performance of ONOOˉ‐potentiated mild‐temperature PTT is validated on subcutaneous and orthotopic hepatocellular carcinoma (HCC) models. This research puts forward an innovative strategy to overcome thermoresistance for mild‐temperature PTT, which provides new inspirations to explore ONOOˉ‐sensitized tumor therapy strategies.