In situ sacrificial growth of metastable copper-enriched nanomedicine for cuproptosis-based synergistic cancer therapy

Cu(I) has recently been identified to possess the ability to disturb mitochondrial tricarboxylic acid cycle and induce programmed cell death, known as cuproptosis. Like other forms of programmed cell death, such as apoptosis and ferroptosis, cuproptosis holds significant potential for anticancer treatment. To implement cuproptosis-based therapy effectively, a crucial consideration is the efficient delivery of an excess amount of Cu(I) to the tumor site while elevating subcellular Cu(I) levels. In this research, we developed metastable copper-enriched nanomedicine, namely Cu2O@CuBTC-DSF@HA nanocomposites (CCDHs), using an in situ sacrificial growth approach, wherein CuBTC metal–organic frameworks (MOFs) were grown by etching the Cu2O core surface. Consequently, CCDHs demonstrated considerably lower stability than intact Cu2O nanocubes and CuBTC MOFs in an acidic environment, exhibiting faster disintegration and Cu(I) release kinetics; however, under a pH of 7.4, CCDHs remained stable without any signs of structural collapse or premature Cu(I) release. In vitro studies confirmed that cuproptosis was the primary mechanism responsible for tumor cell death, and our results indicated that tetraethylthiuram disulfide loaded in CCDHs played a synergistic role in promoting cuproptosis rather than inducing apoptosis. The therapeutic efficacy and biosafety of CCDHs were evaluated at the cellular and animal levels, demonstrating excellent therapeutic efficacy and minimal toxicity.