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.