Colorectal cancer (CRC) is the third most common type of malignancies and the leading cause of tumor death worldwide (Siegel et al., 2017). The statistics showed there were approximately 1800,000 new cases and 881,000 CRC related deaths worldwide in 2018 (Bray et al., 2018). Metastasis was found in 25% of patients at initial diagnosis within five years (Anderson et al., 2019). Oxaliplatin is often used in the first-line treatment against metastatic colorectal cancer, which considerably enhances the efficacy rate of combination therapy to over 50% and results in a considerable increased median survival time (Cremolini et al., 2015, Hewish and Cunningham, 2011). Unfortunately, most patients gradually acquire medication resistance after long-term treatment with oxaliplatin. In addition, survival outcomes for patients with colorectal cancer is very poor, with five years survival rate being<10% (Ciombor et al., 2015, Meads and R.A.G.a.W.S.D., 2009). Hence, there is an urgent need to clarify the mechanism of oxaliplatin resistance and develop a new treatment plan against chemotherapy resistance.

Multiple factors lead to drug resistance in tumor cells, including host factors, gene mutation or epigenetic alterations in cancer cells, etc. (Sui et al., 2013). Autophagy is a critical homeostatic cellular degradation system, which plays an important role in response to metabolic and environmental stresses. Autophagy maintains as well as restores metabolic homeostasis by degrading excessive or dysfunctional proteins and damaged or aged organelles (Chen and White, 2011). Autophagy is essential for the survival of cells, tissues, and organs. It is obvious that modulation of autophagy activity is associated with altered tumorigenesis, tumor progression and response to anti-tumor therapies. In many solid tumors, autophagy could maintain the survival of cancer cells to adapt to metabolic stress and stimulation of chemotherapy drugs, thereby mediating chemotherapeutic drug resistance (Manu et al., 2019). Autophagy is often viewed as an important survival mechanism in response to chemotherapeutics, thus autophagy suppression has been emerged as a promising strategy to improve therapeutic efficacy of chemotherapy (Janku et al., 2011, Rubinsztein et al., 2012). Berbamine (BBM) is the major bioactive component that is extracted from the traditional Chinese herbal medicine Berberis amurensis (Sharma et al., 2021). Studies suggested that BBM has anti-tumor effects in various cancers, including breast cancer, lung cancer and melanoma (Hou et al., 2014, Liang et al., 2009, Wang et al., 2009). Recent research indicates that BBM suppresses autophagy by inhibiting autophagosome lysosome fusion and inducing the accumulation of autophagosomes in breast cancer cells (Fu et al., 2018). This provides a hint as to whether the combination of BBM can reverse the drug resistance of colorectal cancer.

Cancer cells need to obtain more amino acids for protein synthesis to sustain and promote their survival, growth, and proliferation. To meet their demand for additional amino acids, cancer cells upregulate their own amino acid transporters (McCracken and Edinger, 2013). ATB0,+ [SLC6A14 (solute carrier family 6 member 14)] is a Na+/Cl−-coupled amino acid transporter, which transports 18 of the 20 essential amino acids (Karunakaran et al., 2011). Compared to normal tissues, its expression is substantially elevated in tumors (Yao et al., 2020a). It is reported that suppressing ATB0,+ expression in tumor cells could cause amino acid deprivation and inhibit cell proliferation (Scalise et al., 2018). Therefore, targeting this transporter to interfere with the transportation of amino acids into tumor cells may cause cellular starvation, impaired redox homeostasis as well as cell death. In addition, the high expression of the transporter on the cancer cell membrane also provides new ideas for the nano-delivery system (Kou et al., 2018, Kou et al., 2020b). In previous studies, we have shown that ATB0,+ target nanoparticles can be applied for tumor specific drug delivery (Kou et al., 2020a, Yao et al., 2020b). Furthermore, targeting ATB0,+ strengthens anti-tumor effects of nanoparticles in breast cancer (Kou et al., 2022b). Tumors with high malignant and strongly metastatic capacity usually express high levels of amino acid transporters (Bernhardt et al., 2017, Guo et al., 2018, Hafliger and Charles, 2019, Mori et al., 2007). We could inhibit the transport function of ATB0,+ using ATB0,+-targeted nanoparticles. Furthermore, ATB0,+-targeted nanoparticles could influence the function of another transporter through coloading its corresponding high-affinity inhibitor during nanoparticle design. In this research, as shown in Fig. 1, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O + B)@Trp-NPs) to evaluate its anti-tumor effect and clarify the mechanism of drug resistance reversal by inhibiting autophagy.