Beyond apoptosis: Navigating Cancer therapy with cu/Fe-ligand Nano-complexes through Cuproptosis and Ferroptosis

Abstract

Exploiting distinct metal-dependent cell death pathways offers a promising strategy to overcome apoptosis resistance in cancer. This review explores recent advances in metal-ligand nano-complexes, sophisticated platforms engineered to overcome the systemic toxicity and poor bioavailability of free metal ions, selectively triggering two distinct cell death pathways: cuproptosis (copper (Cu)-dependent protein aggregation) and ferroptosis (iron (Fe)-catalyzed lipid peroxidation). The central thesis of this review is the pivotal role of ligand coordination chemistry in tailoring the physicochemical properties, including stability, redox potential, and metal release kinetics that control the mechanistic specificity of these nano-complexes. This review provides a systematic classification of these nano-complexes based on their coordinating donor atoms (O, N, S) to illustrate how molecular configuration translates into selective anticancer efficacy. The development of dual-mode Cu/Fe nano-complexes is further illustrated to exert amplified therapeutic efficacy through the synergistic co-activation of both pathways. Therefore, this review provides a strategic framework for the rational design of next-generation metal-based nanotherapeutics, opening new avenues for precision oncology.