Enhanced chemotherapy in thyroid carcinoma: A MnO₂-silica nanoreactor activated by H₂O₂/GSH for hypoxia relief

Thyroid cancer is the most prevalent endocrine cancer that threats to the health of human being seriously, and characterized with resistance to various therapeutic modalities. The therapeutic efficacy of oxygen-dependent chemotherapy is hindered by hypoxia within tumor tissue heavily. Therefore, the supply of oxygen in situ is an effective strategy to improve the chemotherapeutic outcomes. The emergence of nanomedicine open an novel gate for tumor treatment, however, there is still lack of nanoplatforms for sufficient oxygen supply to improve the chemotherapeutic efficiency. In this study, MnO₂ nanoenzyme was decorated onto glutathione (GSH)-sensitive mesoporous silica, and an intelligent nanoreactor was subsequently constructed by loading saikosaponin-d (SSD) into the mesopore channels and modified with folic acid. Upon targeted delivery to thyroid tumor cells, the Mn²⁺ hydrolyzed from nanoreactor facilitated the decomposition of endogenous H₂O₂ in the tumor, alleviating the hypoxic tumor microenvironment. Simultaneously, the tetrasulfide bonds of silica were cleaved by cytoplasmic L-GSH, releasing the loaded cargoes. 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 attributed to the generation of copious amounts of O₂via disrupting the PI3K/Akt signaling pathway via transcriptome sequencing. The outstanding biocompatibility of the H₂O₂/GSH dual-sensitive Mn-based nanoreactor offered an exceptional chemotherapeutic effect against malignant tumors.