Glutathione-triggered release of SO2 gas to augment oxidative stress for enhanced chemodynamic and sonodynamic therapy.

Recently, gas therapy has emerged as a promising alternative treatment for deep-seated tumors. However, some challenges regarding insufficient or uncontrolled gas generation as well as unclear therapeutic mechanisms restrict its further clinical application. Herein, a well-designed nanoreactor based on intracellular glutathione (GSH)-triggered generation of sulfur dioxide (SO2) gas to augment oxidative stress has been developed for synergistic chemodynamic therapy (CDT)/sonodynamic therapy (SDT)/SO2 gas therapy. The nanoreactor (designed as CCM@FH-DNs) is constructed by employing iron-doped hollow mesoporous silica nanoparticles as carriers, the surface of which was modified with the SO2 prodrug 2,4-dinitrobenzenesulfonyl (DNs) and further coated with cancer cell membranes for homologous targeting. The CCM@FH-DNs can not only serve as a Fenton-like agent for CDT, but also as a sonosensitizer for SDT. Importantly, CCM@FH-DNs can release SO2 for SO2-mediated gas therapy. Both in vitro and in vivo evaluations demonstrate that the CCM@FH-DNs nanoreactor performs well in augmenting oxidative stress for SO2 gas therapy-enhanced CDT/SDT via GSH depletion and glutathione peroxidase-4 enzyme deactivation as well as superoxide dismutase inhibition. Moreover, the doped iron ions ensure that the CCM@FH-DNs nanoreactors enable magnetic resonance imaging-guided therapy. Such a GSH-triggered SO2 gas therapy-enhanced CDT/SDT strategy provides an intelligent paradigm for developing efficient tumor microenvironment-responsive treatments.

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

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.