Nanoscale copper ethoxide enables immunologically enhanced hepatoma radio-immunotherapy via synergistic cuproptosis and metabolic oxidative stress.

Metal alkoxides hold promise in catalysis and materials science, but their rapid hydrolysis in aqueous media represents a major limitation for biomedical applications. To harness this intrinsic reactivity therapeutically, we developed a facile ultrasonication-assisted dispersion method to fabricate nanoscale copper ethoxide (CuOEt) with subsequent screening showing their ready dispersion in Lipiodol to form a stable injectable suspension (CuOEt@LPD). Unlike bare CuOEt nanoparticles, which suffered from rapid degradation, a burst release of ethanol, and conversion to copper oxide in water, the CuOEt@LPD formulation utilized a Lipiodol protection strategy to create an effective barrier against water, enabling a sustained release of ethanol. Functionally, the released ethanol upregulated intracellular cytochrome P450 2E1 (CYP2E1), triggering metabolic oxidative stress in hepatocellular carcinoma cells, which acted synergistically with released copper ion-induced cuproptosis, ultimately leading to robust cell death. Furthermore, the Lipiodol dispersant served as a potent radiosensitizer, significantly enhancing the tumor-inhibiting efficacy upon radiotherapy in an H22 murine hepatoma model. Notably, we discovered that this trimodal therapeutic strategy could also initiate a robust antitumor immune response, which established long-lasting immunological memory, thereby effectively suppressing tumor recurrence and metastasis. Our work successfully establishes metal alkoxides nanoparticles as a highly promising class of nanotherapeutic agents for hepatocellular carcinoma treatment.