Synergistic chemodynamic and metabolic reprogramming-based cancer therapy by CuO@HA nanozymes with oxygen vacancy

<b>Rationale:</b> The tumor microenvironment (TME), which is characterized by disordered metabolism, acidic pH, and high glutathione (GSH) and hydrogen peroxide (H₂O₂) levels, seriously hampers the efficacy of cancer therapy. Nanozymes with multi-enzyme activity have considerable potential to reprogram the TME and suppress tumor growth. <b>Methods:</b> A strategy for remodulating the TME based on a hierarchical CuO nanozyme with oxygen vacancies decorated with hyaluronic acid (HA) (CuO@HA) was developed. The enzyme activities of CuO@HA were evaluated by enzyme kinetic assays and density functional theory (DFT). The <i>in vitro</i> and <i>in vivo</i> anti-tumor effects were estimated, and the mechanism was explored using multi-omic methods. <b>Results:</b> CuO@HA exhibited effective peroxidase (POD)-like enzyme and glutathione oxidase (GSHOx)-like enzyme activities, which catalyzing the decomposition of H₂O₂ into toxic hydroxyl radicals (·OH) and oxidation of GSH into glutathione disulfide (GSSG), respectively. DFT calculations confirmed the effective catalytic activity of CuO@HA. Both <i>in vitro</i> and <i>in vivo</i> experiments demonstrated that CuO@HA can inhibit the growth of breast cancer and melanoma cells with no notable systemic toxicity by producing high levels of ·OH and reprogramming the glycine, serine, and threonine metabolism pathways in tumor tissues. <b>Conclusions:</b> Our study is the first to demonstrate a strategy to reprogram the glycine, serine, and threonine metabolic pathways via the CuO nanoparticle-mediated downregulation of choline dehydrogenase (<i>Chdh</i>) in tumor tissues. This antitumor strategy, which combines chemodynamic therapy and reprogramming of amino-acid metabolism, represents a novel approach for cancer therapy.