Dual H 2 O 2 /GSH-Sensitive MnO 2 -Coated Mesoporous Silica Nanoreactor Fabrication with Saikosaponin-d Loading for Hypoxia Alleviation Enhancing Thyroid Carcinoma Chemotherapy

The O 2 -dependent chemotherapy usually exhibits limited therapeutic efficiency toward hypoxic solid tumors because of inadequate O 2 supply in tumor vasculature. Hence, an O 2 -elevated nanoplatform for delivering chemotherapeutics and eradicating malignant tumors needs to be urgently developed. In this study, MnO 2 nanoenzyme was coated on GSH-sensitive mesoporous silica. Subsequently, an intelligent nanoreactor was constructed after saikosaponin-d (SSD) loading in the mesopore channels and folic acid anchoring on the rough surface. After precise targeting of thyroid tumor cells, the obtained nanoreactor induced the decomposition of tumor endogenous H 2 O 2 to relieve hypoxic tumor microenvironment. In the meantime, the tetrasulfide bonds of silica were broken by cytoplasmic GSH to release the loaded therapeutic molecules. Consequently, a remarkably enhanced chemotherapeutic effect of SSD was achieved both in vitro and in vivo . The mechanism underlying the tumor cell–killing effect was demonstrated to involve massive O 2 generation, which facilitated the interruption of the PI3K/Akt signaling pathway. The outstanding biocompatibility of the H 2 O 2 /GSH dual-sensitive Mn-based nanoreactor offered an exceptional chemotherapeutic effect against malignant tumors.