Hypoxia-Triggered Self-Assembly of Ultrasmall Iron Oxide Nanoparticles to Amplify the Imaging Signal of a Tumor.

Hypoxia is a common phenomenon among most solid tumors that significantly influences tumor response toward chemo- and radiotherapy. Understanding the distribution and extent of tumor hypoxia in patients will be very important to provide personalized therapies in the clinic. Without sufficient vessels, however, traditional contrast agents for clinical imaging techniques will have difficulty in accumulating in the hypoxic region of solid tumors, thus challenging the detection of hypoxia in vivo. To overcome this problem, herein we develop a novel hypoxia imaging probe, consisting of a hypoxia-triggered self-assembling ultrasmall iron oxide (UIO) nanoparticle and assembly-responding fluorescence dyes (NBD), to provide dual-mode imaging in vivo. In this strategy, we have employed nitroimidazole derivatives as the hypoxia-sensitive moiety to construct intermolecular cross-linking of UIO nanoparticles under hypoxia, which irreversibly form larger nanoparticle assemblies. The hypoxia-triggered performance of UIO self-assembly not only amplifies its T2-weighted MRI signal but also promotes the fluorescence intensity of NBD through its emerging hydrophobic environment incorporated into self-assemblies. In vivo results further confirm that our hypoxic imaging probe can display a prompt MRI signal for the tumor interior region, and its signal enhancement performs a long-term effective feature and gradually reaches 3.69 times amplification. Simultaneously, this probe also exhibits obvious green fluorescence in the hypoxic region of tumor sections. Accordingly, we also have developed a MRI difference value method to visualize the 3D distribution and describe the extent of the hypoxic tumor region within the whole bodies of mice. Due to its notable efficiency of penetration and accumulation inside a hypoxic tumor, our hypoxia imaging probe could also be considered as a potential candidate as a versatile platform for hypoxia-targeted drug delivery, and meanwhile its hypoxia-related therapeutic efficacy can be monitored.

A Titanium Nitride Nanozyme for pH-Responsive and Irradiation-Enhanced Cascade-Catalytic Tumor Therapy.

Nanozyme-based catalytic tumor therapy is an emerging therapeutic method with high reactivity in response to tumor microenvironments (TMEs). To overcome the current limitations of deficient catalytic activity of nanozymes, we studied the contributing factors of enzymatic activity based on non-metallic-atom doping and irradiation. Nitrogen doping significantly enhanced the peroxidase activity of Ti-based nanozymes, which was shown experimentally and theoretically. Based on the excellent NIR-adsorption-induced surface plasmon resonance and photothermal effect, the enzymatic activity of TiN nanoparticles (NPs) was further improved under NIR laser irradiation. Hence, an acidic TME-responsive and irradiation-mediated cascade nanocatalyst (TLGp) is presented by using TiN-NP-encapsulated liposomes linked with pH-responsive PEG-modified glucose oxidase (GOx). The integration of pH-responsive GOx-mediated H2 O2 self-supply, nitrogen-doping, and irradiation-enhanced enzymatic activity of TiN NPs and mild-photothermal therapy enables an effective tumor inhibition by TLGp with minimal side effects in vivo.

Polyhydroxylated fullerenols regulate macrophage for cancer adoptive immunotherapy and greatly inhibit the tumor metastasis.

Adoptive immunotherapy is a highly effective approach for cancer treatment. Several potential adoptive immunotherapies have high (though reversible) toxicities with disappointing results. Polyhydroxylated fullerenols have been demonstrated as promising antitumor drugs with low toxicities. In this study, we investigate whether polyhydroxylated fullerenols (C60(OH)22 and Gd@C82(OH)22) contribute to cancer immunotherapy by regulating macrophages. Our results show that fullerenols treatment enhances mitochondrial metabolism, phagocytosis and cytokine secretion. Moreover, activated macrophages inhibit the growth of several cancer cell types. It is likely that this inhibition is dependent on an NF-κB-mediated release of multiple cytokines. Using a lung metastasis model, we also show that autologous macrophages greatly suppress cancer cell metastasis to lung when they are activated by C60(OH)22 and Gd@C82(OH)22. More importantly, Gd@C82(OH)22 are shown to have stronger ability than C60(OH)22 to improve the macrophage function, which shed light on the rational design for nanomedicine and clinical application. FROM THE CLINICAL EDITOR: The interest in the use of immunotherapy in cancer has rekindled recently. However, many approaches have shown disappointing results. In this study, the authors investigated the effects of polyhydroxylated fullerenol nanoparticles on regulating macrophages for immunotherapy. These positive findings may point a novel way to cancer treatment.

Bismuth Sulfide Nanoflowers Facilitated miR339 Delivery to Overcome Stemness and Radioresistance through Ubiquitin-Specific Peptidase 8 in Esophageal Cancer.

Despite the superior efficacy of radiotherapy in esophageal squamous cell carcinoma (ESCC), radioresistance by cancer stem cells (CSCs) leads to recurrence, metastasis, and treatment failure. Therefore, it is necessary to develop CSC-based therapies to enhance radiotherapy. miR-339-5p (miR339) is involved in stem cell division and DNA damage checkpoint signaling pathways based on ESCC cohort. miR339 inhibited ESCC cell stemness and enhanced radiation-induced DNA damage by targeting USP8, suggesting that it acts as a potential CSC regulator and radiosensitizer. Considering the limited circulating periods and poor tumor-targeting ability of miRNA, a multifunctional nanoplatform based on bismuth sulfide nanoflower (Bi@PP) is developed to efficiently deliver miR339 and improve radioresistance. Intriguingly, Bi@PP encapsulates more miR339 owing to their flower-shaped structure, delivering more than 1000-fold miR339 into cells, superior to free miR339 alone. Besides being used as a carrier, Bi@PP is advantageous for dynamically monitoring the distribution of delivered miR339 in vivo while simultaneously inhibiting tumor growth. Additionally, Bi@PP/miR339 can significantly enhance radiotherapy efficacy in patient-derived xenograft models. This multifunctional platform, incorporating higher miRNA loading capacity, pH responsiveness, hypoxia relief, and CT imaging, provides another method to promote radiosensitivity and optimize ESCC treatment.

Three-Dimensional Label-Free Observing of the Self-Assembled Nanoparticles inside a Single Cell at Nanoscale Resolution.

Understanding the intracellular behavior of nanoparticles (NPs) plays a key role in optimizing the self-assembly performance of nanomedicine. However, conducting the 3D, label-free, quantitative observation of self-assembled NPs within intact single cells remains a substantial challenge in complicated intracellular environments. Here, we propose a deep learning combined synchrotron radiation hard X-ray nanotomography approach to visualize the self-assembled ultrasmall iron oxide (USIO) NPs in a single cell. The method allows us to explore comprehensive information on NPs, such as their distribution, morphology, location, and interaction with cell organelles, and provides quantitative analysis of the heterogeneous size and morphologies of USIO NPs under diverse conditions. This label-free, in situ method provides a tool for precise characterization of intracellular self-assembled NPs to improve the evaluation and design of a bioresponsive nanomedicine.

Ferroptosis: challenges and opportunities for nanomaterials in cancer therapy.

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.

Celebrating 20 Years of NCNST: Innovation in Nanoscience and Nanotechnology.

With the development of nanoscience and technology, it has become an essential part of various research directions, changing our way of life, such as advanced accurate manufacturing in nanotechnology that facilitates reducing chip sizes, progress made in health care via nanoscience that provides hope to patients, and so on. As the nation's flagship institution of nanoscience and technology in China, the National Center for Nanoscience and Technology, China (NCNST), established in December 2003, has played a crucial role in promoting cutting-edge technologies in the field of nanoscience and expediting interdisciplinary fusion. With a strong research team and state-of-the-art research equipment, NCNST currently carries out frontier research and world-class technology innovation, including nanosystems and hierarchical fabrication, biological effects of nanomaterials and nanosafety, standardization and measurements for nanotechnology, as well as theoretical simulations. Serving as one of the most prestigious institutions in nanoscience and nanotechnology in China, NCNST will continue to foster impactful international cooperation, cultivate young talents, and boost inspiring innovation.

Designing Smart Iron Oxide Nanoparticles for MR Imaging of Tumors.

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.

Enhanced Glioblastoma Selectivity of Harmine via the Albumin Carrier.

Glioblastoma, the most common tumor in the brain, has witnessed very little clinical progress over the last decades. Exploring and discovering new therapeutic strategies for glioblastoma has become a critical problem. Harmine (HM), belonging to the beta-carboline alkaloid, is a natural product and isolated from the seeds of Peganum harmala L., which own notable antitumor activity in vitro. However, the poor water solubility and less selectivity of HM severely limit its clinical use. For enhancing its selective ability to tumor cells, we fabricated a kind of protein nanoparticles (BSA-HM NPs), composed of the modified bovine serum albumin (BSA) and HM. It was substantiated through in vitro and in vivo experiment that BSA-HM NPs could predominantly accumulate in tumor tissues and exhibited remarkably enhanced antitumor efficacy. This study provides a promising strategy to improve the bioavailability and avoid side effects of HM as antitumor agents by choosing BSA as carriers.

Retraction: Enhanced anti-tumor efficacy of hyaluronic acid modified nanocomposites combined with sonochemotherapy against subcutaneous and metastatic breast tumors.

Retraction of 'Enhanced anti-tumor efficacy of hyaluronic acid modified nanocomposites combined with sonochemotherapy against subcutaneous and metastatic breast tumors' by Pengying Wu et al., Nanoscale, 2019, 11, 11470-11483, https://doi.org/10.1039/C9NR01691K.

Retraction: Cell membrane based biomimetic nanocomposites for targeted therapy of drug resistant EGFR-mutated lung cancer.

Retraction of 'Cell membrane based biomimetic nanocomposites for targeted therapy of drug resistant EGFR-mutated lung cancer' by Pengying Wu et al., Nanoscale, 2019, 11, 19520-19528, https://doi.org/10.1039/C9NR05791A.

Designing Hypoxia-Responsive Nanotheranostic Agents for Tumor Imaging and Therapy.

Hypoxia, a common feature of most solid tumors, plays an important role in tumor proliferation, metastasis, and invasion, leading to drug, radiation, and photodynamic therapy resistance, and resulting in a sharp reduction in the disease-free survival rate of tumor patients. The lack of sufficient blood supply to the interior regions of tumors hinders the delivery of traditional drugs and contrast agents, interfering with their accumulation in the hypoxic region, and preventing efficient theranostics. Thus, there is a need for the fabrication of novel tumor theranostic agents that overcome these obstacles. Reports, in recent years, of hypoxia-responsive nanomaterials may provide with such means. In this review, a comprehensive description of the physicochemical and biological characteristics of hypoxic tumor tissues is provided, the principles of designing the hypoxia-responsive tumor theranostic agents are discussed, and the recent research into hypoxia-triggered nanomaterials is examined. Additionally, other hypoxia-associated responsive strategies, the current limitations, and future prospects for hypoxia-responsive nanotheranostic agents in tumor treatment are discussed.

Tailoring metal-organic frameworks-based nanozymes for bacterial theranostics.

Nanozymes are next-generation artificial enzymes having distinguished features such as cost-effective, enhanced surface area, and high stability. However, limited selectivity and moderate activity of nanozymes in the biochemical environment hindered their usage and encouraged researchers to seek alternative catalytic materials. Recently, metal-organic frameworks (MOFs) characterized by distinct crystalline porous structures with large surface area, tunable pores, and uniformly dispersed active sites emerged, that filled the gap between natural enzymes and nanozymes. Moreover, by selecting suitable metal ions and organic linkers, MOFs can be designed for effective bacterial theranostics. In this review, we briefly presented the design and fabrication of MOFs. Then, we demonstrated the applications of MOFs in bacterial theranostics and their safety considerations. Finally, we proposed the major obstacles and opportunities for further development in research on the interface of nanozymes and MOFs. We expect that MOFs based nanozymes with unique physicochemical and intrinsic enzyme-mimicking properties will gain broad interest in both fundamental research and biomedical applications.

Time-course effect of ultrasmall superparamagnetic iron oxide nanoparticles on intracellular iron metabolism and ferroptosis activation.

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.

Hypoxia and pH co-triggered oxidative stress amplifier for tumor therapy.

To keep fast proliferation, tumor cells are exposed to higher oxidative stress than normal cells and they upregulate the amount of some antioxidants such as glutathione (GSH) against reactive oxygen species to maintain the balance. This phenomenon is severe in hypoxic tumor cells. Although researchers have proposed a series of treatment strategies based on regulating the intracellular reactive oxygen species level, few of them are related to the hypoxic tumor. Herein, a novel organic compound (PLC) was designed by using lysine as a bridge to connect two functional small molecules, a hypoxia-responsive nitroimidazole derivative (pimonidazole) and a pH-responsive cinnamaldehyde (CA) derivative. Then, the oxidative stress amplifying ability of PLC in hypoxic tumor cells was evaluated. The acidic microenvironment of tumor can trigger the release of CA to produce reactive oxygen species. Meanwhile, large amount of nicotinamide adenine dinucleotide phosphate (NADPH) can be consumed to decrease the synthesis of GSH during the bio-reduction process of the nitro group in PLC under hypoxic conditions. Therefore, the lethal effect of CA can be amplified for the decrease of GSH. Our results prove that this strategy can significantly enhance the therapeutic effect of CA in the hypoxic tumor cells.

Tumor-Associated Macrophage and Tumor-Cell Dually Transfecting Polyplexes for Efficient Interleukin-12 Cancer Gene Therapy.

Interleukin 12 (IL12) is a potent pro-inflammatory chemokine with multifunction, including promoting cytotoxic T-cell-mediated killing of cancer cells. IL12-based cancer gene therapy can overcome IL12's life-threatening adverse effects, but its clinical translation has been limited by the lack of systemic gene-delivery vectors capable of efficiently transfecting tumors to produce sufficient local IL12. Macrophages inherently excrete IL12, and tumor-associated macrophages (TAMs) are the major tumor component taking up a large fraction of the vectors arriving in the tumor. It is thus hypothesized that a gene vector efficiently transfecting both cancer cells and TAMs would make the tumor to produce sufficient IL12; however, gene transfection of TAMs is challenging due to their inherent strong degradation ability. Herein, an IL12 gene-delivery vector is designed that efficiently transfects both cancer cells and TAMs to make them as a factory for IL12 production, which efficiently activates anticancer immune responses and remodels the tumor microenvironment, for instance, increasing the M1/M2 ratio by more than fourfold. Therefore, the intravenously administered vector retards tumor growth and doubles survival in three animal models' with negligible systemic toxicities. This work reports the first nonviral IL12 gene delivery system that effectively makes use of both macrophages and tumor cells.

The effect of size and surface ligands of iron oxide nanoparticles on blood compatibility.

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.

Metal ions modulation of the self-assembly of short peptide conjugated nonsteroidal anti-inflammatory drugs (NSAIDs).

Metal ions are essential components that help maintain the processes of normal life, and they can be used to fabricate self-assembled building blocks for peptide derivatives, proteins and nucleic acids. Here, we have developed a novel strategy to construct supramolecular hydrogels modulated using metal cations. Upon introducing a variety of metal ions into aqueous solutions of a gelator (naproxen-FF), including a nonsteroidal anti-inflammatory drug (NSAID) and dipeptide, we obtain stable hydrogels under neutral or alkaline conditions. It is found that these hydrogels with three-dimensional nanofiber networks exhibit excellent mechanical properties and thixotropy, as well as superb responsivity to multiple metal ions. Due to the significance of potassium ions in biological processes, the K-triggered hydrogel has been chosen as a model, and its self-assembly mechanism has been explored via various spectral analysis processes. In addition, the self-assembly performances of peptides are significantly affected by the chemical structures of the gelator molecules. This work provides deep insight into the aggregation mechanism of dipeptide-conjugating drug molecules through introducing a variety of metal ions, laying the foundation for further biological applications.

Gd-metallofullerenol drug delivery system mediated macrophage polarization enhances the efficiency of chemotherapy.

Treatment of solid tumors by chemotherapy is usually failed in clinical because of its low effectiveness and side effects. Stimulation of immune system in vivo to fight cancer has been proved to be a pleasant complementary to systemic chemotherapy. Herein, we have developed a combination cancer therapy strategy by using polymer nanoparticles to deliver Gd-metallofullerenol and doxorubicin simultaneously. The Gd-metallofullerenol provoked the Th1 immune response by regulating the M1 macrophage polarization and the doxorubicin realized direct tumor cells killing by its cytotoxic effect. Also, the Gd-metallofullerenol as part of component in delivery system enhances the encapsulation efficiency of doxorubicin in polymer cargo for potential passive tumor target. The biocompatible and reliable method by combining nanoparticle-induced immune modulation and chemotherapy triggers systemic antitumor immune responses for the synergistic inhibition of tumor growth in vivo. The integration of Gd-metallofullerenol and doxorubicin with potentially complementary functions in one nanoplatform may provide new opportunities to improve cancer treatments.

Few-Layer Bismuthene for Checkpoint Knockdown Enhanced Cancer Immunotherapy with Rapid Clearance and Sequentially Triggered One-for-All Strategy.

As a conceptually attractive strategy, the use of immune checkpoint blockade antibodies to treat cancer is limited due to the restrained tumor-infiltrating lymphocytes (TILs), poor accumulation and penetration of antibodies, and deficient checkpoint blockade in malignancies. In this study, we describe a pH and mild photothermal sequentially triggered PD-L1 siRNA release nanosystem, based on monoelemental bismuthene, as a one-for-all strategy to realize enhanced tumor mild photothermal immunotherapy. Under manually controlled NIR irradiation, the bismuthene-based nanosystem simultaneously induces a tumor-enhanced pathological permeability and retention (EPPR) effect, increases TIL recruitment, and triggers programmed siRNA release, thereby amplifying anti-PD-L1 immunotherapy. In addition, the nanosystem's rapid removal through intestinal and renal clearance mitigates toxicity risk associated with long-term retention. In vivo antitumor experiments demonstrate that this bismuthene-based nanosystem is a promising and effective approach for "cold" tumor management.