Colorectal Tumor Microenvironment‐Activated Bio‐Decomposable and Metabolizable Cu2O@CaCO3 Nanocomposites for Synergistic Oncotherapy

Abstract Rational design of tumor microenvironment (TME)‐activated nanocomposites provides an innovative strategy to construct responsive oncotherapy. In colorectal cancer (CRC), the specific physiological features are the overexpressed endogenous H 2 S and slightly acidic microenvironment. Here, a core–shell Cu 2 O@CaCO 3 nanostructure for CRC “turn‐on” therapy is reported. With CaCO 3 responsive to pH decomposition and Cu 2 O responsive to H 2 S sulfuration, Cu 2 O@CaCO 3 can be triggered “on” into the therapeutic mode by the colorectal TME. When the CaCO 3 shell decomposes and releases calcium in acidic colorectal TME, the loss of protection from the CaCO 3 shell exposes the Cu 2 O core to be sulfuretted by H 2 S to form metabolizable Cu 31 S 16 nanocrystals that gain remarkably strong near‐infrared absorption. After modifying hyaluronic acid, Cu 2 O@CaCO 3 can achieve synergistic CRC‐targeted and TME‐triggered photothermal/photodynamic/chemodynamic/calcium‐overload‐mediated therapy. Moreover, it is found that the generation of hyperthermia and oxidative stress from Cu 2 O@CaCO 3 nanocomposites can efficiently reprogram the macrophages from the M2 phenotype to the M1 phenotype and initiate a vaccine‐like immune effect after primary tumor removal, which further induces an immune‐favorable TME and intense immune responses for anti‐CD47 antibody to simultaneously inhibit CRC distant metastasis and recurrence by immunotherapy.