Ferroptosis is an iron‐dependent, lipid peroxide‐driven cell death caused by inhibition of the cystine/glutamate transporter, which is of importance for the survival of triple‐negative breast cancer (TNBC) cells. Erastin is a low molecular weight chemotherapy drug that induces ferroptosis; however, poor water solubility and renal toxicity have limited its application. Exosomes, as drug delivery vehicles with low immunogenicity, high biocompatibility and high efficiency, have attracted increasing attention in recent years. Herein, we developed a formulation of erastin‐loaded exosomes labeled with folate (FA) to form FA‐vectorized exosomes loaded with erastin (erastin@FA‐exo) to target TNBC cells with overexpression of FA receptors. The characterization, drug release, internalization and anti–tumor effect in vitro of erastin@FA‐exo were determined. Erastin@FA‐exo could increase the uptake efficiency of erastin into MDA‐MB‐231 cells; compared with erastin@exo and free erastin, erastin@FA‐exo has a better inhibitory effect on the proliferation and migration of MDA‐MB‐231 cells. Furthermore, erastin@FA‐exo promoted ferroptosis with intracellular depletion of glutathione and reactive oxygen species overgeneration. Western blot analyses revealed that erastin@FA‐exo suppressed expression of glutathione peroxidase 4 (GPX4) and upregulated expression of cysteine dioxygenase (CDO1). We conclude that targeting and biocompatibility of exosome‐based erastin preparations provide an innovative and powerful delivery platform for anti–cancer therapy.

Although ferroptosis has been recognized as a novel antitumoral treatment, high expression of nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to be an antioxidant transcript factor that protects malignant cells from ferroptosis. Previous findings indicated that metallothionein 1D pseudogene (MT1DP), a long noncoding RNA (lncRNA), functioned to aggravate oxidative stress by repressing antioxidation. Here we aimed at assessing whether MT1DP could regulate erastin-induced ferroptosis on non-small cell lung cancer (NSCLC) and elucidating the mechanism. We found that ectopic expression of MT1DP sensitized A549 and H1299 cells to erastin-induced ferroptosis through downregulation of NRF2; in addition, ectopic MT1DP upregulated malondialdehyde (MDA) and reactive oxygen species (ROS) levels, increased intracellular ferrous iron concentration, and reduced glutathione (GSH) levels in cancer cells exposed to erastin, whereas downregulation of MT1DP showed the opposite effect. RNA pulldown assay and dual-luciferase reporter assay confirmed that MT1DP modulated the expression of NRF2 via stabilizing miR-365a-3p. As low solubility of erastin limits its efficient application, we further prepared folate (FA)-modified liposome (FA-LP) nanoparticles for targeted co-delivery of erastin and MT1DP to enhance the bioavailability and the efficiency of the drug/gene combination. Erastin/MT1DP@FA-LPs (E/M@FA-LPs) sensitized erastin-induced ferroptosis with decreased cellular GSH levels and elevated lipid ROS. In vivo analysis showed that E/M@FA-LPs had a favorable therapeutic effect on lung cancer xenografts. In short, our findings identify a novel strategy to elevate erastin-induced ferroptosis in NSCLCs acting through the MT1DP/miR-365a-3p/NRF2 axis.

Selenium nanoparticles (SeNPs) have attracted increasing interest over the last decades because of their activities on redox balance in human body. However, the SeNPs tend to aggregate into large clusters, resulting in lower bioactivity, bioavailability and biocompatibility. Surface-capping agents on SeNPs play crucial roles in its stabilization and biological activity. Here, a green synthesis method for the preparation of Lycium barbarum polysaccharides capped SeNPs using green tea extracts as reductants under mild conditions, at room temperature, is reported. The structure, size, morphology and thermal behaviour were analyzed by various characterization techniques. The functionalized nanoparticles demonstrated high antioxidant activity, including DPPH and ABTS free radical scavenging. Moreover, the SeNPs significantly protected the HO-induced PC-12 cell death. Taken together, these results evidence the possible application of these SeNPs as antioxidants food supplement or ingredient and neuroprotective agent.

Growing evidence confirms that ferroptosis plays an important role in tumor growth inhibition. However, some non‐small‐cell lung cancer (NSCLC) cell lines are less sensitive to erastin‐induced ferroptotic cell death. Elucidating the mechanism of resistance of cancer cells to erastin‐induced ferroptosis and increasing the sensitivity of cancer cells to erastin need to be addressed. In our experiment, erastin and acetaminophen (APAP) cotreatment inhibited NSCLC cell viability and promoted ferroptosis and apoptosis, accompanied with attenuation of glutathione and ectopic increases in lipid peroxides. Erastin and APAP promoted NSCLC cell death by regulating nucleus translocation of nuclear factor erythroid 2‐related factor 2 (Nrf2); and the ferroptosis induced by erastin and APAP was abrogated by bardoxolone methyl (BM) with less generation of reactive oxygen species and malondialdehyde. As a downstream gene of Nrf2, heme oxygenase‐1 expression decreased significantly with the cotreatment of erastin and APAP, which could be rescued by BM. In vivo experiment showed that the combination of erastin and APAP had a synergic therapeutic effect on xenograft of lung cancer. In short, the present study develops a new effective treatment for NSCLC by synergizing erastin and APAP to induce ferroptosis.