Tetra-Sulfide-Bridged Cerium-Based Nanozyme with Macrophage Membrane Camouflage for Enhanced Reactive Oxygen Species Generation via GSH Depletion and O ₂ Supply

The high intracellular glutathione (GSH) level, naturally hypoxic conditions within the tumor microenvironment, and limited reactive oxygen species (ROS) generation pose significant obstacles to the effectiveness of sonodynamic therapy (SDT). Overcoming these barriers through depletion of GSH and relieving hypoxia offer a promising strategy to enhance SDT effectiveness. Herein, we developed a dendritic tetra-sulfide-bridged mesoporous silica (DTSMO) that encapsulated both chlorin e6 (Ce6) and cerium via channel-limited in situ coordination and is subsequently cloaked with the macrophage cell membrane (MCM) to facilitate efficient reactive oxygen species (ROS)-based therapy via multispecies enzymatic activities. First, this nanosystem exhibited Ce(IV) ions to mimic catalase (CAT)-like activity, converting H₂O₂ into O₂, thereby effectively alleviating tumor hypoxia. Meanwhile, the nanosystem possessed Ce (III)-based peroxidase (POD)-like activity, enabling the conversion of H₂O₂ into hydroxyl radicals (^•OH) while simultaneously depleting GSH. Both in vitro and in vivo experiments demonstrated that GSH depletion exerted a powerful supplementary effect on CDT and SDT, achieving a tumor inhibition rate of up to 96%, without affecting normal tissues during treatment.