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 H2S and slightly acidic microenvironment. Here, a core–shell Cu2O@CaCO3 nanostructure for CRC “turn‐on” therapy is reported. With CaCO3 responsive to pH decomposition and Cu2O responsive to H2S sulfuration, Cu2O@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 Cu2O core to be sulfuretted by H2S to form metabolizable Cu31S16 nanocrystals that gain remarkably strong near‐infrared absorption. After modifying hyaluronic acid, Cu2O@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 Cu2O@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.

A tumor microenvironment responsive nanosystem for chemodynamic/chemical synergistic theranostics of colorectal cancer

“…It is an effective and innovative strategy to construct a tumor microenvironment responsive nanosystem by rational design 43 , 44 . Several studies have manifested that tumor microenvironment responsive nanosystem based on the specific physiological features of colorectal cancer offers a paradigm in the synergistic treatment of colorectal cancer 45 , 46 . As previously reported 36 , Mn-O bonds enriched in MNSN can be cracked by GSH as shown by TEM, resulting in the release of Mn 2+ .…”

Chemodynamic nanomaterials for cancer theranostics

“…Both inorganic materials and organic materials can be used as photothermal materials. Inorganic materials mainly include the noble metals (e.g., Au, Ag, and Pt), metal chalcogenides (e.g., CuS), and carbon-based nanomaterials [ 161 , 162 ]. Organic photothermal materials mainly include small molecule dyes (e.g., indocyanine green, prussian blue) and conjugated polymers (e.g., polyaniline, polypyrrole, polythiophene, polydopamine) [ 163 – 165 ].…”

Artificial Engineering of Immune Cells for Improved Immunotherapy

“…[ 38,39 ] Apart from targeting specific pathways, including CD47–SIRPα signaling using antibody‐based therapeutics, [ 37–41 ] researchers excavated multifunctional materials and biomimetic strategies to activate macrophages for antitumor immunotherapy. [ 42,43 ] A core–shell Cu 2 O@CaCO 3 nanostructure was designed for targeted and TME‐triggered multiple combination therapy, where macrophages were activated in response to hyperthermia and oxidative stress for synergistic antitumor effect. [ 42 ] Learning from natural pathogens, a plant virus‐like particle assembled from Cowpea chlorotic mottle virus was designed for targeted delivering oligodeoxynucleotides adjuvant for macrophage modulation.…”

“…[ 42,43 ] A core–shell Cu 2 O@CaCO 3 nanostructure was designed for targeted and TME‐triggered multiple combination therapy, where macrophages were activated in response to hyperthermia and oxidative stress for synergistic antitumor effect. [ 42 ] Learning from natural pathogens, a plant virus‐like particle assembled from Cowpea chlorotic mottle virus was designed for targeted delivering oligodeoxynucleotides adjuvant for macrophage modulation. [ 43 ]…”