Copper‐Based Bio‐Coordination Nanoparticle for Enhanced Pyroptosis‐Cuproptosis Cancer Immunotherapy through Redox Modulation and Glycolysis Inhibition

Copper-based nanoparticles have garnered significant interest in cancer therapy due to their ability to induce oxidative stress and cuproptosis in cancer cells. However, their antitumor effectiveness is constrained by the dynamic redox balance and the metabolic shift between oxidative phosphorylation and glycolysis. Here, a polydopamine-coated copper-α-ketoglutaric acid (α-KG) coordination polymer nanoparticle (CKPP) is designed for combined pyroptosis-cuproptosis cancer immunotherapy by amplifying reactive oxygen species (ROS) production and regulating cellular metabolism. The intracellular redox imbalance is achieved through the synergistic effects of α-KG-induced mitochondrial metabolic reprogramming, photothermally enhanced superoxide dismutase-like activity of polydopamine, and glutathione depletion by copper ions. The multifaceted redox modulation results in a substantial increase in intracellular ROS levels, triggering oxidative stress and subsequent pyroptosis in cancer cells. Furthermore, α-KG shifts cellular metabolism from glycolysis to oxidative phosphorylation, thereby enhancing cuproptosis induced by copper ions. The combination of ROS dyshomeostasis and glycolysis inhibition results in a potent enhancement of pyroptosis-cuproptosis-mediated cancer therapy. In a murine model of colorectal cancer, CKPP exhibited a remarkable anticancer effect, achieving a tumor inhibition rate of 96.3% and complete tumor eradication in two out of five cases. Overall, this bio-engineered metal-organic nanocomposite demonstrates significant potential for treating cancer through combined pyroptosis-cuproptosis cancer immunotherapy.