Mitochondria- and anaerobic glycolysis-targeted self-assembled copper complex nanoparticles for boosting cuproptosis-immunotherapy

Cuproptosis is an emerging regulated cell death that depends on the intracellular copper ion and mitochondrial respiration, showing great potential in cancer treatment. However, increasing the specific accumulation of copper ions in mitochondria while simultaneously enhancing mitochondrial respiration is highly needed and still a major challenge to promote cuproptosis. Herein, the lactate dehydrogenase (LDH) inhibitor galloflavin (GF) self-assembles with the copper ionophore elesclomol (ES) through copper ion-driven cooperative coordination to form GF/CuES hybrid nanoparticles, synergistically targeting mitochondria and anaerobic glycolysis to boost cuproptosis-immunotherapy. After cellular internalization, the GF/CuES hybrid nanoparticles responsively dissociate to release Cu²⁺ and ES, co-transporting into mitochondria to collaboratively trigger cuproptosis, which subsequently evokes immunogenic cell death (ICD). Notably, the liberated GF leads to effective LDH suppression, which not only further amplifies cuproptosis via disrupting anaerobic glycolysis and enhancing mitochondrial respiration but also reduces lactate production, thus alleviating the immunosuppressive tumor microenvironment and augmenting anti-tumor immunity driven by ICD. Thus, the GF/CuES hybrid nanoparticles exhibit strong antitumor effects through cooperatively targeting glycolysis, cuproptosis, and immunotherapy, offering a unique opportunity to enhance cancer treatment strategies.