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

作者：Yang Li, Jinyan Lin, Peiyuan Wang, Fukai Zhu, Ming Wu, Qiang Luo, Yun Zhang, Xiaolong Liu · 发表于：ACS Nano · 年份：2022 · DOI：10.1021/acsnano.1c09496 · 被引用次数：77 · 研究领域：Nanoplatforms for cancer theranostics、MXene and MAX Phase Materials、Advanced Nanomaterials in Catalysis

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 t...