Active-transporting of charge-reversal Cu(II)-doped mesoporous silica nanoagents for antitumor chemo/chemodynamic therapy

Fe-based Fenton agents can generate highly reactive and toxic hydroxyl radicals (·OH) in the tumor microenvironment (TME) for chemodynamic therapy (CDT) with high specificity. However, the low pH environment and insufficient endogenous hydrogen peroxide (H2O2) of the highly efficient Fenton reaction limits its practical application in clinic. Here, a Cu(II)-doped mesoporous silica nanoagent (Cu-MSN) with excellent dispersity was successfully developed. After loaded with doxorubicin (DOX) and ascorbate (AA), Cu-MSN@DA was coated with active targeting ligand folic acid (FA), dimethyl maleic an-hydride (DMMA) and carboxymethyl chitosan (CMC) to obtain an active transporting nanoagent (FCDC@Cu-MSN@DA) with tunable charge-reversal property, which is more adaptable to the pH value of TME than Fe-based Fenton agents, and can self-supply exogenous H2O2 by ascorbate to produce more toxic ·OH to trigger the apoptosis of cancer cells. Meanwhile, the high level of glutathione (GSH) in TME can reduce Cu(II) to Cu(I) by Fenton-like reaction, increasing the generation rate of ·OH and relieving tumor antioxidant ability. The supply of exogenous H2O2 significantly enhanced the synergistic effect of CDT by oxidative damage. Together with DOX-induced cell apoptosis, this novel nanoagent FCDC@Cu-MSN@DA can achieve maximum therapeutic efficacy, creating a new model of safe and effective tumor treatment with high specificity.