A nano-engineered approach to elicit ferroptosis/cuproptosis/apoptosis in tumor combination therapy

• pH-responsive CuO 2 -DSF@ZIF-8 (CDZ NCs) enable targeted copper delivery to tumors, triggering cuproptosis while minimizing off-target toxicity. • In situ-formed CuET and Cu + induce apoptosis, cuproptosis, and ROS generation, synergistically killing cancer cells. • CDZ NCs effectively suppress tumor growth by activating cuproptosis/ferroptosis/apoptosis pathways in vivo . Cuproptosis, a copper-dependent programmed cell death, provides opportunities for copper-enriched nanomaterials to achieve cancer therapy. However, existing copper-delivery systems are hampered by critical limitations, such as nonspecific copper release, insufficient endogenous substrates, especially hydrogen peroxide (H 2 O 2 ), all of which restrict their therapeutic efficacy. Herein, a pH-responsive nano-delivery system (CuO 2 -DSF@ZIF-8, CDZ NCs) was developed via integrated multifunctional design to address above issues, enabling targeted copper delivery for synergistic induction of cuproptosis, ferroptosis and apoptosis. The core–shell architecture of CDZ NCs enables pH-responsive targeted release of cargos, in which the ZIF-8 shell remains stable in neutral healthy tissues but degrades rapidly in the acidic tumor microenvironment, preventing premature drug leakage and reducing off-target toxicity. Encapsulated CuO 2 acts as an in-situ H 2 O 2 generator via catabolism, overcoming the insufficient endogenous H 2 O 2 levels in tumors which would otherwise limit the induction of ferroptosis. Meanwhile, the co-loaded disulfiram (DSF) reacts synergistically with released Cu 2+ , forming cytotoxic bis(diethyldithiocarbamate)copper (CuET) to induce apoptosis and drive Cu 2+ -to-Cu + conversion. The generated Cu + further amplifies therapeutic effects through triggering mitochondrial lipoylated protein aggregation-mediated cuproptosis, as well as accelerating ferroptosis. Collectively, this integration of pH sensitivity, H 2 O 2 self-supply, and multi-pathway crosstalk enbles CDZ NCs as a powerful weapon for enhanced cancer therapy.