Globally, cervical cancer is a major health concern for women, with about 604,000 new cases and 342,000 deaths estimated in 2020 worldwide according to the up-to-date global data (Sung et al., 2021). For the standard treatment for advanced cervical cancer, NCCN guidelines recommend a combination of radiotherapy and cisplatin-based chemotherapy (Koh et al., 2019). Currently, radiotherapy has been established as mainstream for the treatment of recurrent and advanced cervical cancers (Lin et al., 2022, Ren et al., 2022). Radiotherapy (RT) induces DNA damage to cause the death of cancer cells directly through DNA ionization and indirectly through stimulating the generation of reactive oxygen species (ROS) (O'Connor, 2015). Double-strand DNA breaks induced by radiation therapy could promote the activation of DNA damage response signaling pathways consisting of DNA damage repair and cell cycle checkpoint control (Huang and Zhou, 2020).

Unfortunately, the efficacy of radiotherapy is always limited due to the inherent or acquired radioresistance, which commonly leads to tumor recurrence, metastasis and poor prognosis of cancer patients, being the treatment bottleneck in radiotherapy and radiochemotherapy (Huang et al., 2021, Sun et al., 2021). According to previous researches, cancer radioresistance is the process by which cancer cells or tissues adjust to the changes induced by radiation therapy and manifest resistance to the ionizing radiation (Cai et al., 2023). It contains multiple mechanisms, such as DNA damage and repair, oncogene and tumor suppressor alterations, tumor microenvironment changes, cell cycle arrest, tumor heterogeneity, autophagy, hypoxia, cancer stem cells, and metabolic alteration (Ali et al., 2020, Busato et al., 2022, Zeng et al., 2020).

More importantly, emerging evidence have identified a close relationship between death receptors (DR4 and DR5) and cancer radioresistance. One study found that microRNA-1246 contributed to the radioresistance of lung cancer cells by directly inhibiting DR5 gene (Buck et al., 2021, Yuan et al., 2016). In addition, ionizing radiation pretreatment could upregulate the expression levels of DR4 and DR5 at the transcription stage for many cancers (Hori et al., 2010). Due to the overexpression of DR4 and DR5 in cancer cells and few in normal cells, many drugs of agonistic antibodies against DR4 or DR5 have been exploited for cancer therapy including radiotherapy (Zhang et al., 2019, Zheng et al., 2023). Tumor necrosis factor - related apoptosis-inducing ligand (TRAIL), belonging to tumor necrosis factor gene family, can specifically target DR4 and DR5 to induce cancer cell apoptosis by triggering a caspase-dependent apoptosis pathway (Singh et al., 2021, Yuan et al., 2018). TRAIL exhibits cancer-killing ability but shows low toxicity against normal cells, which is conferred an ideal therapeutic characteristic (Deng and Shah, 2020). Emerging evidence has demonstrated TRAIL expression contributed to the cancer radiosensitivity. For example, Baijer et. al (Baijer et al., 2016) reported that radiosensitive T4EM lymphocytes displayed a higher expression of TRAIL mRNA and membrane bound TRAIL in comparison with radioresistant T4EM lymphocytes. In a recent study, it was reported that TRAIL overexpression could induce apoptosis to accelerate the radiosensitivity of breast cancer MDA-MB-231 cells (Xu et al., 2022). Hence, TRAIL has been developed as a potential therapeutic agent for treating radioresistant cancers. Yet, due to the insufficient accumulation in cancer cells and resistance of tumor cells to TRAIL, TRAIL-mediated antitumor role is still ineffective in clinical trials to date (Alizadeh Zeinabad and Szegezdi, 2022), for which an effective drug delivery system should be developed (Gao et al., 2021).

Simultaneously, more and more radiosensitizers have been developed to overcome the radioresistance in various cancers. Especially, high level of glutathione (GSH) has been shown to clear ROS to facilitate the cervical cancer radioresistance (Zhou et al., 2019) and induce drug release (Mo and Gu, 2016), therefore development of radiosensitizers based on downregulating antioxidants may be a therapeutic strategy for treating cervical cancer (Dai et al., 2023). Among various radiosensitizers, copper-based nanomaterials have drawn extensive interests due to their tremendous potential in enzyme-like activities including glutathione oxidase and peroxidase, which induce GSH degradation and ROS production (Yu et al., 2020, Zhao et al., 2020). Peroxidase mainly catalyzes substrate oxidation with H2O2 as the electron acceptor (Kopecka et al., 2021). Moreover, many nanomaterials possess peroxidase-like activity. Among them, Cu2−xSe, as the product of copper and Se nanoparticles, has been the research hotspot in recent years, because not only they have excellent photothermal performance but also Cu and Se element are essential trace elements for human body (Ge et al., 2022, Green, 2018, Zhang et al., 2021a). For example, Wang et al. (Wang et al., 2021) reported that PEG-Cu2−xSe HNCs could induce ·OH overproduction via Fenton-like reaction in the use of H2O2, leading to hepatoma cells apoptosis. Regretfully, few Cu2−xSe nanomaterials have clinical applications because of some limitations such as lack of immune evasion, poor tumor targeting, low cellular uptake and unavoidable damage to adjacent normal body tissues.

Hence, tumor-specific targeting strategies was being more and more critical. As the cell membrane based-camouflaged nanotechnology develops, a biomimetic drug delivery system has been demonstrated as a promising alternative to achieve the specific targetability (Zhang et al., 2023). Recently, cell membranes implied for encapsulating nanoparticles mainly derives from red blood cells, platelets, neutrophils, macrophages, cancer cells, T lymphatic cells and stem cells (Li et al., 2022, Oroojalian et al., 2021, Xu et al., 2020). In particular, due to a series of proteins on cancer cell membranes, cancer cell membrane-camouflaged nanomaterials possess specific tumor-homing capability and prolonged circulation time, which have obtained superiority in cervical cancer treatment (Harris et al., 2019, Zeng et al., 2022). For example, Zhang et al. (Zhang et al., 2021b) used nanosized cancer cell membranes with CD47 overexpression (meTGCT) to camouflage Ti3C2 nanosheets for achieving powerful homologous targeting capacities and immune evasion. On this basis, for effectively inducing cancer-killing response and targeting efficacy to cancer tissues of TRAIL, a method of decorating cell membranes with TRAIL and simultaneously used it to package nanoparticle was recommended.

Inspired by this concept, we constructed a TRAIL-overexpressed cervical cancer cells through genetic bioengineering, and then prepared cervical cancer cell membrane- camouflaged Cu2−xSe nanomedicine (CCMT) for reversing the radioresistance of cervical cancer (Schema 1). The cancer cell membrane functionalized with TRAIL modification endowed Cu2−xSe with the abilities of immune evasion and targeting to cervical cancer cell. For assessing the capability of CCMT in reversing the radioresistance of cervical cancer, we also constructed radioresistant cervical cancer cell line through gradual increase of radiation dose. Then, the mechanisms of radioresistance in cervical cancer was elucidated. Furthermore, in vitro and in vivo experiments elaborated that CCMT could accumulate in homogenous radioresistant HeLa cells with excellent abilities of immune evasion and achieve strong radiosensitization together with antitumor effect in cervical cancer.