The revolutionizing osteosarcoma therapy of carbon monoxide and doxorubicin synergy via mesoporous silica nanoparticles

Chemoresistance is the main cause of recurrence and metastasis in osteosarcoma patients; therefore, efficient therapeutic measures need to be developed to reverse chemoresistance. In this study, we designed and synthesized selenium-hybrid degradable hollow mesoporous silica nanoparticles (SeNPs) to simultaneously encapsulate doxorubicin (DOX) and carbon monoxide (CO)-releasing molecule-3 (CORM-3), and modified their surfaces with polyethylene glycol (PEG) via disulfide bonds (SeNP-PEG@DOX-CO). Subsequently, after incubation with SeNP-PEG@DOX-CO, DOX was effectively delivered into 143B cells, and CO was released in the mitochondria under the stimulation of high concentrations of glutathione (GSH) and reactive oxygen species (ROS). All in vitro anticancer functional experiments and animal experiments confirmed that DOX had CO-enhanced antitumor efficacy and that CO cooperated with chemotherapeutic drugs to resist tumors. Meanwhile, we provided for the first time a combined proteomic and metabolomic landscape of CO reversing chemotherapy resistance in osteosarcoma. This study revealed a revolutionizing osteosarcoma therapy to treat resistance for chemotherapy.