Harnessing nanomedicine to orchestrate ferroptosis-cuproptosis crosstalk for precision antitumor therapy: Novel insights and future perspectives

Abstract

The efficacy of conventional antitumor monotherapies that target ferroptosis and cuproptosis is limited, highlighting the urgent need for the development of novel therapeutic strategies. Recent studies have demonstrated significant synergistic interactions between these cell death pathways, which are mediated by dysregulated iron and copper metabolism, increased oxidative stress via Fenton reactions and copper-dependent reactive oxygen species (ROS), and mitochondrial dysfunction characterized by lipid peroxidation (LPO) and degradation of iron‐sulfur (Fe-S) clusters. To harness this synergy, addressing the challenges associated with targeted coactivation is essential. This review provides a systematic analysis of the molecular interplay between ferroptosis and cuproptosis and an evaluation of the crucial role of advanced nanodelivery systems, such as polymeric nanoparticles (NPs), biocompatible materials, metal organic frameworks, and inorganic NPs, in facilitating this dual activation. These multifunctional nanocarriers enable spatiotemporally controlled drug delivery and the integration of multimodal therapeutic strategies, including photodynamic therapy (PDT), photothermal therapy (PTT), sonodynamic therapy (SDT), chemotherapy, chemodynamic therapy (CDT), radiotherapy (RT), and immunotherapy. Finally, we explore the translational prospects and challenges of this new therapeutic approach in targeted cancer therapy, emphasizing its promise in transforming precision oncology.