Unraveling the Crosstalk Between Ferroptosis and Cuproptosis for Rational Nanomedicine Design in Cancer.

Ferroptosis and cuproptosis constitute two key metal-dependent regulated cell death pathways with distinct execution mechanisms, yet they exhibit intricate crosstalk revolving around glutathione (GSH) metabolism, iron‑sulfur cluster proteins, and shared regulators such as Nrf2 and FDX1. Co‑activating both pathways can overcome compensatory resistance and create a self‑amplifying lethal cascade. Nanomedicine provides an enabling platform to exploit this interplay through rationally designed nanotherapeutics that achieve spatiotemporally controlled metal ion delivery, tumor microenvironment‑responsive release, and integration with external stimuli or immunotherapy. This review delineates the molecular convergence of ferroptosis and cuproptosis, presents a framework for rational nanomedicine design based on prioritized disabling of antioxidant defenses and sequential activation strategies, and surveys representative nanoplatforms including copper‑based nanozymes, bimetallic nanoparticles, ionophore‑loaded regulators, and endogenous metal mobilizers. The synergy with photothermal, sonodynamic, and immune checkpoint blockade therapies is also discussed, highlighting immunogenic cell death induction and the conversion of "cold" tumors into "hot" ones. The work further clarifies current challenges and future perspectives toward clinical translation, thus providing a practical framework to inspire the rational design of next‑generation metal‑based nanomedicines.