P-glycoprotein suppression by photothermal-responsive nitric oxide releasing nanoplatform for triple-combination therapy of multidrug resistant cancer

Multi-drug resistance (MDR) in tumor therapy often leads to relatively low efficiency of the current chemotherapeutics, attributing to the overexpression of P-glycoprotein (P-gp) increases the efflux of anticancer drugs out of the cells. To address this obstacle, herein, a photothermal-triggered nitric oxide (NO) gas releasing nanosystem was designed for reversing drug resistance in MDR cells based on mesoporous core–shell structured nanocomposites (MCSN) of Cu2-x[email protected]2. The mesoporous shell provided the modification and encapsulation capacity for the NO donor—S-nitrosothiol (SNO) and doxorubicin (DOX) loading. Besides, the heat generated from the photothermal conversion of Cu2-xSe could trigger NO gas generation and enhance DOX release in the acid microenvironment of cancer cells. The released NO gas in the cytoplasm could induce mitochondrial dysfunction to block adenosine triphosphate (ATP) synthesis and ATP-dependent drug efflux, thereby overcoming MDR. Therefore, this novel gas/chemo/photothermal triple-combination therapeutic nanoplatform is expected to be a potentially effective strategy against MDR and may reveal new insights for other NO gas-relevant medical applications.