Construction of a pH-responsive nanoreactor and its specific inhibition of oral squamous cell carcinoma growth via TME and xCT/GSH/GPX4 axis

Abstract

Abstract Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in oral and maxillofacial region, distinguished by its formidable invasiveness, high incidence of lymph node metastatic, and unfavorable prognosis. Given the current dearth of specific drugs, effectively curtailing its growth, invasion, and metastasis poses a significant challenge. The tumor microenvironment (TME) exhibits mildly acidic conditions and a high concentration of H2O2, which makes the use of this characteristic for cancer treatment a promising cancer treatment approach. In this study, we developed a pH-responsive nanoreactor, composed of ultrasmall Prussian blue nanoparticles within mesoporous calcium-silicate nanoparticles (USPBNs@MCSNs, UPM). This innovative nanoreactor converted endogenous H2O2 in TME into abundant ·OH while generating oxygen in non-tumor regions to reduce hypoxia-induced chemotherapy resistance. The findings showed UPM induced OSCC cells ferroptosis by downregulated the xCT/GPX4/GSH axis, effectively restraining the growth, migration, and invasion of OSCC cells, and did not cause systemic toxicity. Consequently, the pH-responsive UPM synthesized here possesses the ability to initiate specific biochemical reactions in TEM, and has potential clinical application value.