Smart Porous Core–Shell Cuprous Oxide Nanocatalyst with High Biocompatibility for Acid‐Triggered Chemo/Chemodynamic Synergistic Therapy

Abstract The rational integration of chemotherapy and hydroxyl radical (·OH)‐mediated chemodynamic therapy (CDT) holds great potential for cancer treatment. Herein, a smart biocompatible nanocatalyst based on porous core–shell cuprous oxide nanocrystals (Cu 2 O‐PEG (polyethylene glycol) NCs) is reported for acid‐triggered chemo/chemodynamic synergistic therapy. The in situ formed high density of hydrophilic PEG outside greatly improves the stability and compatibility of NCs. The porosity of Cu 2 O‐PEG NCs shows the admirable capacity of doxorubicin (DOX) loading (DOX@Cu 2 O‐PEG NCs) and delivery. Excitingly, Cu (Cu +/2+ ) and DOX can be controllably released from DOX@Cu 2 O‐PEG NCs in a pH‐responsive approach. The released Cu + exerts Fenton‐like catalytic activity to generate toxic ·OH from intracellular overexpressed hydrogen peroxide (H 2 O 2 ) for CDT via reactive oxygen species (ROS)‐involved oxidative damage. Exactly, DOX can not only induce cell death for chemotherapy but also enhance CDT by self‐supplying endogenous H 2 O 2 . After the intravenous injection, Cu 2 O‐PEG NCs can effectively accumulate in tumor region via passive targeting improved by external high‐density PEG shell. Additionally, the effect of boosted CDT combined with chemotherapy presents excellent in vivo antitumor ability without causing distinct systemic toxicity. It is believed that this smart nanocatalyst responding to the acidity provides a novel paradigm for site‐specific cancer synergetic therapy.