Ferroptosis, a completely new form of regulated cell death, is mainly caused by an imbalance between oxidative damage and reductive protection and has shown great anti-cancer potential. However, existing small-molecule ferroptosis inducers have various limitations, such as poor water solubility, drug resistance and low targeting ability, hindering their clinical applications. Nanotechnology provides new opportunities for ferroptosis-driven tumor therapy. Especially, stimuli-responsive nanomaterials stand out among others and have been widely researched because of their unique spatiotemporal control advantages. Therefore, it’s necessary to summarize the application of those stimuli-responsive nanomaterials in ferroptosis. Here, we describe the physiological feature of ferroptosis and illustrate the current challenges to induce ferroptosis for cancer therapy. Then, nanomaterials that induce ferroptosis are classified and elaborated according to the external and internal stimuli. Finally, the future perspectives in the field are proposed. We hope this review facilitates paving the way for the design of intelligent nano-ferroptosis inducers.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely used and have attracted increased attention for their unique physicochemical properties, especially in biomedical sciences as contrast agents following intravenous administration. However, only few studies have systematically reported the blood compatibility of iron oxide nanoparticles with different physicochemical properties such as different sizes and surface ligands. Therefore, we selected three widely used organic ligands (polyacrylic acid, hyaluronic acid, and chitosan) with modified SPIONs at the same size of 5–6 nm, and polyacrylic acid-modified SPIONs with different sizes (5, 10, and 30 nm) at different concentrations to evaluate their haemocompatibility. Our results revealed that SPIONs modified with polyacrylic acid demonstrated size-dependent destruction of red blood cells and complement activation. Interestingly, 5 nm SPIONs prolonged blood clotting time as compared with 10 nm and 30 nm SPIONs in vitro. Compared with polyacrylic acid-modified SPIONs, hyaluronic acid- and chitosan-modified SPIONs least affected red blood cells, platelets, coagulation, and complement activation. Hence, hyaluronic acid- and chitosan-coated SPIONs are more suitable for nanomedicine applications than polyacrylic acid-coated SPIONs. Furthermore, the interaction between SPIONs and blood components strongly correlated with the administered concentration of nanoparticles. These results will provide some experimental information for safe-by-design SPIONs.

Iron oxide nanoparticles (IONPs) possess unique magnetism and good biocompatibility, and they have been widely applied as contrast agents (CAs) for magnetic resonance imaging (MRI). Traditional CAs typically show a fixed enhanced signal, thus exhibiting the limitations of low sensitivity and a lack of specificity. Nowadays, the progress of stimulus-responsive IONPs allows alteration of the relaxation signal in response to internal stimuli of the tumor, or external stimuli, thus providing an opportunity to overcome those limitations. This review summarizes the current status of smart IONPs as tumor imaging MRI CAs that exhibit responsiveness to endogenous stimuli, such as pH, hypoxia, glutathione, and enzymes, or exogenous stimuli, such as magnets, light, and so on. We discuss the challenges and future opportunities for IONPs as MRI CAs and comprehensively illustrate the applications of these stimuli-responsive IONPs. This review will help provide guidance for designing IONPs as MRI CAs and further promote the reasonable design of magnetic nanoparticles and achieve early and accurate tumor detection.

The therapeutic efficacy of anti-cancer nanomedicines is generally constrained due to limited accumulation in the solid tumors. In this study, we developed a biomimetic nano-carrier to enhance the chemo-therapeutic efficacy of doxorubicin and icotinib in a chemo-resistant non-small cell lung cancer (NSCLC) cell line harboring a mutation in the epidermal growth factor receptor (EGFR). The unique nanomedicine was prepared by coating with targeting cancer cell membrane proteins as highly specific ligands. The resulting biomimetic nanoparticles were highly stable and exhibited superior homologous targeting ability in vitro compared with control groups. In a mouse EGFR-mutated NSCLC xenograft model, intravenous injection of the biomimetic nanomedicine led to a high tumour inhibition rate (87.56%). Histopathological analysis demonstrated that the biomimetic nanomedicine had minimal side effects. Taken together, a cancer cell membrane-based biomimetic drug carrier can significantly enhance drug accumulation and improve therapeutic efficacy in cancers.

Ferroptosis is an iron-dependent cell death caused by excessive peroxidation of polyunsaturated fatty acids. It can be activated by iron-based nanoparticles as a potential cancer therapeutic target. However, the intracellular transformation of iron-based nanoparticles is still ambiguous and the subsequent ferroptosis mechanism is also obscure. Here, we identified the time-course metabolism of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) in cells by using X-ray absorption near edge structure spectroscopy. Also, the integrated quantitative transcriptome and proteome data obtained from the cells exposed to USPIO exhibited hallmark features of ferroptosis. With the chemical species of iron oxide transforming to ferritin, the intracellular GPX4 down-regulated, and lipid peroxide began to accumulate. These results provide evidence that the intracellular metabolism of USPIO induced ferroptosis in a time-dependent manner, and iron over-loaded in cytoplasm along with lipid peroxidation of the membrane are involved in the detailed mechanism of ferroptosis signaling activation.