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. Pentacarbonyl 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.

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