Reactive oxygen species nanoamplifiers with multi-enzymatic activities for enhanced tumor therapy

Abstract

The ingenious combination of nano-enzymes with multi-enzyme activities and therapeutic drugs that can promote reactive oxygen species (ROS) production in cancer cells will enhance the therapeutic efficacy of nanomedicines on malignant tumors by amplifying oxidative stress. Herein, PEGylated Ce-doped hollow mesoporous silica nanoparticles (Ce-HMSN–PEG) loaded with saikosaponin A (SSA) are elaborately constructed as a smart nanoplatform for improving the efficiency of tumor therapy. The carrier Ce-HMSN–PEG showed multi-enzyme activities due to the presence of mixed Ce³⁺/Ce⁴⁺ ions. In the tumor microenvironment, peroxidase-like Ce³⁺ ions convert endogenous H₂O₂ into highly toxic ˙OH for chemodynamic therapy, while Ce⁴⁺ ions not only show catalase-like activity to reduce tumor hypoxia but also exhibit glutathione (GSH) peroxidase-mimicking properties to effectively deplete GSH in tumor cells. Moreover, the loaded SSA can cause the enrichment of superoxide anions (˙O₂⁻) and H₂O₂ within tumor cells by disrupting mitochondrial functions. By integrating the respective advantages of Ce-HMSN–PEG and SSA, the as-prepared SSA@Ce-HMSN–PEG nanoplatform can efficiently trigger cancer cell death and inhibit tumor growth via significantly enhanced ROS production. Therefore, this positive combination therapy strategy has a good application prospect for enhancing antitumor efficacy.