Metal-Phenolic Nanoplatform Tailored to the Metabolic Dependence of Prostate Cancer to Amplify Cuproptosis and Apoptosis

A copper-phloretin nanoplatform (Cu-Phl MPN) selectively targets respiration-active prostate cancer cells through cuproptosis vulnerability. • Cu-Phl MPNs block GLUT1-mediated glucose uptake, suppressing copper efflux and chelation to amplify intracellular Cu + accumulation. • The nanoplatform synergistically triggers apoptosis and cuproptosis, achieving potent antitumor efficacy with high biosafety. Prostate cancer (PCa) cells, characterized by sustained high mitochondrial respiratory activity following malignant transformation, possess intrinsic sensitivity to cuproptosis, rendering them suitable candidates for cuproptosis-induced therapies. By exploiting this metabolic vulnerability, tumor microenvironment-responsive copper-based metal-phenolic networks (Cu-Phl MPNs) were developed via self-assembly of Cu 2+ and phloretin to synergistically induce of apoptosis and cuproptosis in respiration-active PCa cells. Following cellular internalization, Cu-Phl MPNs underwent glutathione (GSH) responsive degradation, co-releasing Cu + and Phl. The liberated Phl specifically interrupted GLUT1-mediated intracellular glucose supply, suppressing ATP and NADPH synthesis. ATP depletion downregulated the copper exporter ATP7A and curbed copper efflux, while impaired NADPH production compromised GSH regeneration and diminished copper chelation, collectively facilitating intracellular Cu + accumulation. The accumulated Cu + drove a Fenton-like reaction to generate reactive oxygen species, which disrupted redox homeostasis and triggered mitochondrial apoptosis. Meanwhile, cuproptosis could be efficiently activated under the combination of excess Cu + and inherent sensitivity. Both in vitro and in vivo results demonstrated that Cu-Phl MPNs exerted potent and selective antitumor efficacy against respiration-active LNCaP cells while exhibiting minimal toxicity toward glycolysis-dependent PC3 cells, with favorable biosafety profiles. This work presents a metabolism-directed nanoplatform that aligns therapeutic mechanisms with tumor intrinsic features for precision PCa therapy. Download: Download high-res image (197KB) Download: Download full-size image