Dual-functional copper nanoplatform potentiates cuproptosis through p53 reactivation and metabolic reprogramming

Cuproptosis, a copper-dependent form of regulated cell death driven by mitochondrial metabolism, holds promise as a therapeutic strategy for cancer. However, its efficacy is hampered by tumor metabolic heterogeneity and mutant p53 (mut-p53)-driven metabolic rewiring that blunts cuproptosis sensitivity. Here, we report the rational design of CuF16@246, an acid-responsive, dual-functional copper-based nanocoordination polymer that integrates Cu²⁺ and the p53 reactivator eprenetapopt (APR-246) within a single perfluorosebacic acid (PFSEA)-coordinated framework to synergistically induce cuproptosis and reverse tumor metabolic reprogramming. CuF16@246 comprises a PFSEA-coordinated copper framework with good colloidal stability and pH-dependent co-release of Cu²⁺ and APR-246, enabling controlled Cu²⁺ release and in situ APR-246 loading. Mechanistically, CuF16@246 triggers hallmarks of cuproptosis, including dihydrolipoamide S-acetyltransferase (DLAT) oligomerization and the depletion of the iron‑sulfur (Fe-S) cluster proteins ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS), while APR-246 converts mut-p53 toward a wild-type-like, DNA-binding-competent state, upregulates metabolic targets such as TP53-induced glycolysis and apoptosis regulator (TIGAR) and glutaminase 2 (GLS2), suppresses glycolysis, and enhances tricarboxylic acid (TCA) cycle flux, thereby sensitizing tumor cells to cuproptosis. In vitro and in vivo studies demonstrate that CuF16@246 exhibits more efficient cellular uptake, more potent cytotoxicity, and more significant tumor growth inhibition than individual treatments, without inducing hemolysis or major organ toxicity. This work establishes a dual-functional strategy that combines metabolic reprogramming with sensitized cuproptosis, providing a promising framework for developing advanced copper-based nanomedicines for the treatment of mut-p53-positive cancers.