Metal-organic frameworks for Cuproptosis-based Cancer therapy

Cuproptosis, a recently identified form of regulated cell death, triggers proteotoxic stress through copper-induced aggregation of lipoylated proteins and disruption of iron–sulfur (Fe-S) cluster proteins in the tricarboxylic acid cycle, offering a promising avenue to overcome drug resistance. Though several recent reviews have touched upon nanomaterials for cuproptosis, in this review, we provide the first comprehensive analysis that specifically dedicated to leveraging the unique structural tunability of Metal-Organic Frameworks (MOFs) to precisely trigger this pathway. Unlike generic nanocarriers, MOFs offer distinct advantages through their adjustable porosity, high surface area, and versatile functionalization, which can trigger cuproptosis in tumors by rationally engineering to maximize intracellular copper influx, inhibit efflux, or deplete glutathione (GSH) and glucose with high specificity. We highlight how the multifunctionality of MOFs facilitates synergistic combinatorial therapies, integrating cuproptosis with photodynamic, photothermal, chemodynamic, sonodynamic, radiotherapy, and immunotherapies. Beyond merely summarizing existing literature, this review critically evaluates the structure-activity relationships between MOFs physicochemical properties and cuproptosis efficiency. Crucially, we provide a critical discussion on the intrinsic limitations and translational hurdles of MOFs, including issues of aqueous stability, potential metal ion leaching toxicity, in vivo circulation half-life, and tumor-specific targeting accuracy. In a word, this review aims to provide thoughtful insights and a rational design framework for the next generation of MOF-based cuproptosis inducers, ultimately guiding their path toward clinical application.