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.