Programmed self-assembly of enzyme activity-inhibited nanomedicine for augmenting chemodynamic tumor nanotherapy

The satisfactory therapeutic effects of chemodynamic therapy (CDT) dependent solely on endogenous hydrogen peroxide (H₂O₂) from tumor cells are difficult to achieve. This is closely attributed to the high metabolic activity of malignant cancer cells, prompting the rapid self-protection and proliferation. Here, we report a programmed self-assembly multilayered nanostructure, thioglycolic acid (TGA)-Cu coordination nanoparticles with rapid GSH-response characteristics, for intensifying the CDT efficiency and comprehensively inhibiting the tumor metabolic activity via exchanging the TGA ligand with glutathione (GSH) in the tumor cell. In the formulation, TGA, a small toxic molecule, was combined with Cu ions and securely delivered to the destination for inactivating the functional protein by depriving their spatial structure, then inducing the inhibition of metabolism and meiosis. Simultaneously, the oxidative stress that originated from the oxidized glutathione (GSSG)-Cu complex triggering H₂O₂ compels the cancer cells to perform active and passive death processes in concert with the inhibition of intracellular enzyme activities. Thus, this work is not only expected to be a heuristic strategy for amplifying the therapeutic effect of CDT together with the inhibition of enzyme activity, but also may advance the construction of stimulus-response bio-functional materials.