Tumor Microenvironment-Responsive Yolk–Shell NaCl@Virus-Inspired Tetrasulfide-Organosilica for Ion-Interference Therapy via Osmolarity Surge and Oxidative Stress Amplification

Ion-interference therapy, which utilizes ions to disturb intracellular biological processes, provides inspiration for tumor therapy. Artificially reversing osmotic pressure by transporting large amounts of physiological ions to tumor cells is a straightforward yet low-toxic strategy for ion-interference therapy. However, it is hard to achieve due to the serious limitations of single-ion delivery. Herein, we skillfully deliver NaCl nanocrystals to tumor sites and sequentially realize the explosive release of Na⁺/Cl^- inside tumor cells by utilizing a virus-mimicking and glutathione (GSH)-responsive hollow mesoporous tetrasulfide-bridged organosilica (ssss-VHMS). Once the ssss-VHMS-wrapped NaCl nanocrystals (NaCl@ssss-VHMS) accumulate in the tumors, they would rapidly invade tumor cells via spike surface-assisted endocytosis, thus bypassing Na⁺/K⁺-ATPase transmembrane ion transporters. Afterward, the intracellular overproduced GSH of tumor cells would trigger the rapid degradation of ssss-VHMS via thiol-tetrasulfide exchange, which could not only remarkably deplete the GSH but also explosively release the Na⁺/Cl^-, leading to the osmolarity surge accompanied by reactive oxygen species (ROS) generation. The cell swelling, ROS storm, and GSH exhaustion of NaCl@ssss-VHMS effectively eradicated tumor cells by caspase-1-dependent pyroptosis, caspase-3-dependent apoptosis, and GPX4-dependent ferroptosis, respectively, thus synergistically inhibiting tumor growth. We believe that NaCl@ssss-VHMS would be a potential cancer therapeutic agent, and this discovery could provide a perspective for exploring synergistic ion-interference therapy.