Ultrasmall Copper–Gallic Acid Nanodots for Chemodynamic Therapy

Abstract An ultrasmall chemodynamic therapeutic (CDT) agent with favorable specificity to tumor microenvironment, i.e., high level of glutathione (GSH) and hydrogen peroxide (H 2 O 2 ), is reported. The coordination polymer nanodot between divalent copper (Cu 2+ ) and gallic acid (GA) is shortly named as Cu–GA. The ultrasmall size of Cu–GA (2.16 ± 0.3 nm) results in a large specific surface area, which is beneficial for improving its catalytic performance. After endocytosis into tumor cell interior, Cu–GA promotes GSH‐activated and H 2 O 2 ‐reinforced CDT in situ, wherein divalent Cu(II) is reduced to monovalent Cu(I) by GSH and induced GSH depletion. Subsequently, the generated Cu(I) catalyzes local H 2 O 2 to generate toxic hydroxyl radical (•OH) via Fenton‐like reaction, and •OH leads to tumor cell apoptosis. The higher levels of GSH and H 2 O 2 in the tumor cell interior significantly improve the efficiency of CDT, and meanwhile protect the normal cells. In addition, the ultrasmall size of Cu–GA facilitates its fast clearance and eliminates long‐term body retention, with minimized systemic toxicity during the treatment in vivo. Therefore, as a novel copper‐based nanoformulation specifically responsive to the tumor microenvironment, Cu–GA provides promising potentials in CDT.