Cuproptosis nanoprodrug-initiated self-promoted cascade reactions for postoperative tumor therapy.

Cancer metastasis and recurrence remain a regular cause of postoperative death in patients, implying that extra consolidation treatment strategies are needed. Here, a cuproptosis nanoprodrug, termed as Lipo@CP@DQ NPs, is developed to initiate self-promoted cascade reactions to achieve the combinational effect of cuproptosis, in situ chemotherapy, and oxidative stress amplification for effectively suppressing tumor recurrence and metastasis after postoperative treatment. Lipo@CP@DQ NPs are fabricated by loading copper peroxides (Cu2O2, CP) and hydrogen peroxide (H2O2)-repsonsive prodrug DQ into liposomal nanoparticles. Lipo@CP@DQ NPs rapidly dissociate in the acidic tumor microenvironment to release copper ions, H2O2, and prodrug DQ. Subsequently, the excessive accumulation of Cu ions induces cuproptosis and produces highly cytotoxic hydroxyl radicals (•OH). Meanwhile, the self-supplied H2O2 catalyzes the decomposition of DQ to diethyldithiocarbamate (DTC), which is chelated with self-supplied Cu ions to form the anticancer compound, Cu(DTC)2. The another decomposition product, quinone methide (QM), acts as a glutathione (GSH) scavenger for oxidative stress amplification. The synergistic effect of Lipo@CP@DQ NPs-mediated cuproptosis, in situ chemotherapy, and oxidative stress amplification effectively inhibits the growth and postoperative recurrence of triple-negative breast cancer. This work furnishes a strategy for developing cuproptosis-based nanomedicines for effective antitumor treatment after surgery.