Emerging nanodelivery systems for cuproptosis induction: design strategies and multidimensional regulatory mechanisms

Cuproptosis, a newly discovered copper-dependent cell death mechanism, has emerged as a research hotspot in cancer therapy in recent years due to its unique metabolic intervention properties and profound interactions with the tumor microenvironment (TME). However, challenges persist in the precise delivery of cuproptosis-inducing agents, metabolic regulation, and synergistic integration with other treatment modalities. Here, we systematically review the latest advances in cuproptosis-based nanotherapeutic strategies for antitumor applications from the perspective of nano-delivery systems. We systematically categorize commonly employed copper ionophores, including small-molecule drug carriers, polymeric copper complexes, metal-organic frameworks (MOFs), inorganic copper-based nanoparticles, and composite/hybrid delivery systems. We further analyze optimization strategies for their physicochemical properties and delivery efficiency. Importantly, we provide an in-depth discussion on the multidimensional regulatory mechanisms of cuproptosis-based nanotherapies: targeting copper metabolism regulation; disrupting tumor metabolic reprogramming; cross-regulation with other programmed cell death pathways; remodeling the TME; and integration with energy-mediated physical therapies to achieve spatiotemporally controlled copper release and synergistic effects. This review aims to provide a theoretical foundation for the rational design of cuproptosis-based nanotherapies, bridging the gap between fundamental research and clinical applications.