Ovarian cancer has seriously threatened the lives and health of women (Xia et al., 2022), with chemotherapy being the first-line treatment (Armstrong et al., 2021). However, due to the non-specific distribution of chemotherapy drugs, the resulting organ toxicity has seriously affected the quality of life of patients. Additionally, chemotherapy predisposes to drug resistance development in tumor cells, leading to tumor recurrence or metastasis and reducing the survival rate of patients (Kuroki and Guntupalli, 2020). The main cause of chemotherapy failure is multidrug resistance (MDR) development, which is the most significant challenge in tumor therapy. Studies have reported that MDR is correlated with several factors, including high expression and activity of adenosine triphosphate (ATP) binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) (Das et al., 2021, Khalifa et al., 2019). The process by which P-gp excretes chemotherapy drugs is highly ATP-dependent (Kim and Chen, 2018, Kodan et al., 2021, Wang et al., 2021a). Furthermore, ATP is involved in several biological metabolic pathways, including tumor cell proliferation. Accordingly, targeting tumor energy metabolism is one of the potential strategies to reverse MDR (Guo et al., 2023, Hong et al., 2013, Kabanov et al., 2003, Liang et al., 2021).

Normally differentiated cells produce energy for cellular processes primarily through mitochondrial oxidative phosphorylation (OXPHOS), while most tumor cells rely on aerobic glycolysis, known as the Warburg effect (Warburg et al., 1927). However, recent studies have demonstrated that while most tumor cells rely on glycolysis for energy production, their mitochondrial function remains intact. The OXPHOS pathway can continue to produce sufficiently high ATP levels (Vaupel and Multhoff, 2021). Besides, the Warburg effect can be activated by the overproduction of mitochondrial reactive oxygen species (ROS) (Cui et al., 2018, Xu et al., 2022). This suggests that the energy supply pathways in tumor cells are not singular and can be interconverted into each other by adapting to different environments and conditions. Drug-resistant ovarian cancer cells have been indicated to favor OXPHOS for energy production over glycolysis (Zampieri et al., 2020). There have been several strategies to reverse MDR by targeting mitochondrial energy metabolism, including mitochondria-associated gene expression inhibition, mitochondrial membrane disruption, and mitochondrial electron transport chain (ETC) blocked (Chen et al., 2021, Luo et al., 2021). Synthetic lethality is the genetic principle that two genetic interferences together are lethal even though neither is lethal on its own. Therefore, in tumor cell energy metabolism, only one energy metabolism pathway is inhibited. Tumor cells can maintain cell activity by converting energy metabolism pathways, ultimately leading to ineffective MDR reversal (Kaur et al., 2021, Wang et al., 2021b, Zacksenhaus et al., 2017). However, the anti-tumor efficiency can be substantially improved when combined with another energy metabolism inhibition method. Therefore, synthetic lethality offers new perspectives for reversing tumor MDR (Dong et al., 2022).

Atovaquone (ATO), an FDA-approved anti-malarial drug, can inhibit complex III activity in the tumor cell mitochondrial ETC, effectively inhibiting the OXPHOS process and reducing ATP production (Gao et al., 2022, Guo et al., 2021). Furthermore, it could inhibit P-gp expression in some breast cancer-resistant cells (Lu et al., 2022). This elucidates that ATO may regulate energy metabolism pathways in drug-resistant ovarian cancer cells, thereby reversing drug resistance. Quercetin (QUE) is a flavonoid commonly found in fruits and vegetables, which has a favorable safety profile and has also received much attention as a glycolysis inhibitor (Reyes-Farias and Carrasco-Pozo, 2019). The QUE has been reported to be able to inhibit glycolytic metabolism by suppressing hexokinase II (HK II ) during glycolysis, thereby hindering glycolytic metabolism to reduce ATP production. In addition, QUE could downregulate P-gp expression in drug-resistant cells (Li et al., 2018, Wu et al., 2019). Therefore, we assumed that energy metabolism pathway co-inhibition by ATO and QUE may promote energy depletion of chemo-resistant tumor cells to facilitate MDR reversal.

Herein, a PLGA-PEG nanoplatform was employed to co-loaded chemotherapeutic agent paclitaxel (PTX), OXPHOS inhibitor (ATO), and glycolysis inhibitor (QUE) to form PTX-ATO-QUE nanoparticles (PAQNPs) (Scheme 1A). After being taken up by tumor cells, PLGA-PEG degrades to release PTX, ATO, and QUE. These compounds are expected to inhibit the mitochondrial OXPHOS and glycolysis processes, respectively, leading to cellular energy depletion. Meanwhile, the reduced ATP content could inhibit P-gp activity, enhancing the PTX-induced chemotherapy to reverse MDR (Scheme 1B). Consequently, this co-delivery nanoplatform can provide a valuable reference for MDR reversal in ovarian cancer.