Engineering Assembly of Metal-Phenolic Nanoparticles with High Biocompatibility for Tumor Therapy

Metal-phenolic nanoparticles have attracted extensive attention for their remarkable properties. However, existing strategies for assembling these nanoparticles often face challenges, including using toxic organic solvents, low biosafety caused by templates, and complex synthesis procedures. Herein, we directly construct a library of metal-phenolic nanoparticles using diverse metal ions and polyphenols assembled in aqueous solutions without templating or seeding agents. We select pH-responsive tea polyphenol-copper nanoparticles (E-Cu NPs) for tumor therapy. In tumor microenvironment, characterized by low pH and high glutathione (GSH) levels, epigallocatechin gallate (EGCG) and Cu²⁺ are released from E-Cu NPs. Cu²⁺ subsequently reacts with GSH to generate Cu⁺, which further catalyzes a Fenton-like reaction to produce hydroxyl radical. The decreased intracellular GSH levels and the disruption of redox homeostasis cause decreased intracellular adenosine triphosphate levels, inhibition of glutathione peroxidase 4 activity, mitochondrial dysfunction, and cuproptosis, which is characterized by the aggregation of lipoylated mitochondrial protein. Additionally, EGCG can be oxidized and bind to glyceraldehyde-3-phosphate dehydrogenase, generating toxic quinoprotein that further induces severe tumor oxidative stress <i>in vivo</i>. Notably, the production of quinoprotein is a distinct pathway that we have identified for the antitumor activity of these polyphenol-based biomaterials. Importantly, E-Cu NPs demonstrate high biocompatibility in cells, zebrafish, nematodes, and mice. Collectively, the library of metal-phenolic nanoparticles constructed through a simple and rapid assembly approach offers various alternatives for biomedical applications.