Thermal-Responsive Carbon Monoxide (CO) Delivery Expedites Metabolic Exhaustion of Cancer Cells toward Reversal of Chemotherapy Resistance

Multidrug resistance (MDR) is the main cause of chemotherapy failure, and the mechanism of MDR is largely associated with drug efflux mediated by the adenosine triphosphate (ATP)-binding cassette transporters. Herein, an NIR-light-triggered CO release system based on mesoporous Prussian blue nanoparticles (PB NPs) was developed to reverse MDR via CO-induced metabolic exhaustion. Penta-carbonyl iron (Fe(CO)(5)) as the CO producer was coupled to PB NPs via coordination interaction, and doxorubicin (Dox) was encapsulated into the pores of PB NPs. After layer-by-layer (LBL) coating, the NPs showed desired serum stability to enhance tumor accumulation. Upon tumor-site-specific NIR light (808 nm) irradiation, the nonlethal temperature elevation cleaved the Fe-CO bond to release CO. CO then expedited mitochondrial metabolic exhaustion to block ATP synthesis and inhibit ATP-dependent drug efflux, thus reversing MDR of the Dox-resistant MCF-7/ADR tumors to potentiate the anticancer efficacy of Dox. In the meantime, CO-mediated mitochondrial exhaustion could upregulate the proapoptotic protein, caspase 3, thus inducing cellular apoptosis and enabling a synergistic anticancer effect with chemotherapy. To the best of our knowledge, this is the first time MDR has been overcome using a CO delivery system. This study provides a promising strategy to realize an effective and safe treatment against MDR tumors and reveals new insights in the use of CO for cancer treatment.