Reducing the availability of endogenous copper and glucose for cascade starvation therapy and chemodynamic therapy

The rapid growth of tumors relies heavily on a continuous supply of essential nutrients, including glucose and copper. Disrupting the nutrient supply to tumors has become an increasingly focal point in tumor therapy. However, solely blocking the energy supply typically only hinders further tumor growth and may not effectively eliminate existing tumor cells. Herein, a multifunctional cascade nanoreactor (HPP/TPEN@GC) endowed with N, N, N', N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN, a copper chelator) and glucose oxidase (GOx) is designed to disrupt both glycolysis and mitochondrial metabolism, which further induce cascade chemodynamic therapy (CDT). HPP/TPEN@GC can react with endogenous copper and glucose, thereby reducing their availability. The absence of copper prevents proper assembly and function of mitochondrial complex IV (CIV), hindering mitochondrial metabolism; the lack of glucose cuts off glycolysis and leads to a tumor specific starvation. Meanwhile, the reactions catalyzed by HPP/TPEN@GC contribute to the generation of Fenton-like catalysts and hydrogen peroxide (H₂O₂), which can further react to produce highly toxic hydroxyl radical (·OH) for CDT. Taken together, the multifunctional cascade nanoreactor reduces the availability of endogenous copper and glucose, and further takes advantage of them to generate ·OH for cascade starvation-chemodynamic therapy. Collectively, this work represents a distinctive therapeutic paradigm to harness endogenous copper and glucose, which should inspire further studies to take full advantage of endogenous nutrients to combat various diseases, including tumors.