Liver cancer stem cells (LCSCs) constitute a distinct subset within liver cancer, possessing the remarkable ability of self-renewal and differentiation [1]. Numerous studies have shown that LCSCs exhibit resistance to chemotherapy and radiation therapy, and their presence in liver cancer is strongly correlated with disease recurrence [2,3]. Therefore, it is imperative to develop effective therapeutic strategies targeting LCSCs to prevent the recurrence and metastasis of liver cancer.

In recent years, combination therapy involving chemotherapy and phototherapy has emerged as a promising technique for enhancing the efficacy of cancer treatment and reducing drug resistance [4]. Salinomycin (SAL), a polyether antibiotic, exhibits potent cytotoxicity against cancer cells that are resistant to conventional chemotherapy drugs [5]. Furthermore, SAL can selectively inhibit the growth of various cancer stem cells (CSCs) [[6], [7], [8]]. Our previous studies have demonstrated the effective inhibition of migration and stemness properties of LCSCs by SAL [9,10]. However, the limited water solubility of SAL poses a hindrance to its clinical application [11]. Moreover, SAL lacks tumor tissue specificity and systemic administration may result in significant toxicity and side effects on normal tissues [12].

Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), is a non-invasive therapeutic approach that can induce local hyperthermia effects and/or generate reactive oxygen species (ROS), resulting in tumor eradication [13]. Several studies have demonstrated the limited efficacy of radiotherapy and chemotherapy in targeting CSCs, while thermotherapy has shown promise in eradicating these cells and inhibiting their stem cell-like properties [14,15]. IR780 is a newly developed photosensitive material with excellent near-infrared (NIR) light absorption and photothermal conversion capabilities. It can absorb NIR light, which is less harmful to the human body, and convert it into heat, causing cancer cells to heat up rapidly and die [16,17]. Moreover, IR780 emits highly intense fluorescence within the wavelength range of 807–823 nm, making it suitable for imaging applications [18,19]. However, its hydrophobic nature and rapid clearance, along with potential acute toxicity at high doses and limited tumor uptake, also impose restrictions on the utilization of IR780 [19]. Therefore, an efficient delivery method is required for the targeted transportation of SAL and IR780 to tumor tissue or cells; however, this aspect has received limited research attention thus far.

Upconversion nanoparticles (UCNPs) are an emerging class of fluorescent probe materials capable of emitting high-energy photons upon excitation by low-energy near-infrared (NIR) light [20]. In recent years, UCNPs have gained significant attention in the fields of bioimaging, photodynamic therapy (PDT), photocatalytic, and three dimensions (3D) display due to their excellent optical stability, remarkable chemical stability, and low toxicity [[20], [21], [22]]. Moreover, similar to various other nanomaterials, UCNPs with a large surface area, unique structures, and versatile surface chemistries have attracted interest as promising drug nanocarriers [23]. Wang et al. were the first to utilize UCNPs as carriers for delivering anti-cancer drugs in chemotherapy and demonstrated that doxorubicin can be loaded onto the surface of PEGylated UCNPs via hydrophobic interactions and be released under a slightly acidic environment [24]. Additionally, UCNPs with a unique upconverted emission wavelength can function as light transducers to activate photosensitizers for deep-tissue photodynamic therapy (PDT) or act as phototriggered devices enabling remote control of drug release induced by NIR light [25].

In this study, we utilized UCNPs as a nanocarrier for drug delivery to specifically target liver cancer cells and LCSCs. SAL and IR780 were encapsulated within UCNP/distearoyl phosphorethanolamine-polyethylene glycol (DSPE-PEG) via hydrophobic interaction. The antitumor activity and mechanisms of the SAL and IR780-loaded UCNPs (UISP) were investigated in vitro.