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 H₂ S and slightly acidic microenvironment. Here, a core-shell Cu₂ O@CaCO₃ nanostructure for CRC "turn-on" therapy is reported. With CaCO₃ responsive to pH decomposition and Cu₂ O responsive to H₂ S sulfuration, Cu₂ O@CaCO₃ can be triggered "on" into the therapeutic mode by the colorectal TME. When the CaCO₃ shell decomposes and releases calcium in acidic colorectal TME, the loss of protection from the CaCO₃ shell exposes the Cu₂ O core to be sulfuretted by H₂ S to form metabolizable Cu₃₁ S₁₆ nanocrystals that gain remarkably strong near-infrared absorption. After modifying hyaluronic acid, Cu₂ O@CaCO₃ 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 Cu₂ O@CaCO₃ 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.