Biomimetic Copper Sulfide for Chemo‐Radiotherapy: Enhanced Uptake and Reduced Efflux of Nanoparticles for Tumor Cells under Ionizing Radiation

Combined chemo‐radiotherapy is one of most widely applied treatments for clinical cancer therapy. Herein, it is found in this carefully designed study that ionizing radiation (e.g., X‐ray) can significantly increase the cell uptake of many different types of nanoparticles, and meanwhile obviously reduce their efflux. Such a phenomenon, which is not observed for small molecule drug such as doxorubicin (DOX), may be attributed to the X‐ray‐induced cell cycle change and upregulation of Caveolin‐1, a key protein in the caveolin‐dependent endocytosis pathway. Biomimetic copper sulfide nanoparticles, which are synthesized using melanin as the template and functionalized with polyethylene glycol (PEG), are then chosen as a platform for the combined chemo‐radiotherapy. Such CuS@Melanin‐PEG nanoparticles, while being able to load chemotherapeutics (e.g., DOX), can also act as a radiosensitizer to promote X‐ray induced cell apoptosis. In addition, although the overall tumor accumulation of CuS@Melanin‐PEG/DOX post intravenous injection is not significantly changed for tumors exposed to X‐ray, X‐ray radiation can result in obviously increased tumor cell uptake of drug‐loaded nanoparticles, subsequently leading to excellent synergistic antitumor therapeutic effect. A nanoplatform is developed with great performance in chemo‐radiotherapy, as well as uncovers a general synergistic mechanism particularly suitable for nanoparticle‐based chemo‐radiotherapy.