Search

Chelators are commonly used to remove excess iron in iron-loading disorders. Deferoxamine (DFO) is an effective and safe iron chelator but an onerous parenteral administration regimen limits its routine use. To develop more effective methods for delivering iron chelators, we examined whether amphiphilic copolymer nanoparticles (NPs) could deliver DFO more efficiently. Physical characterization showed a uniform and stable preparation of DFO nanoparticles (DFO-NPs) with an average diameter of 105.3 nm. In macrophage (RAW264.7) and hepatoma (HepG2) cell lines, DFO-NPs proved more effective at depleting iron than free DFO. In wild-type mice previously loaded with iron dextran, as well as Hbbth3/+ and Hfe–/– mice, which are predisposed to iron loading, DFO-NPs (40 mg/kg DFO; alternate days; 4 weeks) reduced hepatic iron levels by 71, 46, and 37%, respectively, whereas the equivalent values for free DFO were 53, 7, and 15%. Staining for tissue iron and urinary iron excretion confirmed these findings. Pharmacoki...

Platinum (Pt)-based chemotherapy is a widely used therapeutic regimen against various cancers. However, the insufficient cellular uptake, deactivation by thiol-containing species and nonspecific distribution of cisplatin (CDDP) result in its low chemosensitivity as well as systemic side effects, which can largely constrain the employment of CDDP in clinical treatment. To circumvent these problems, in this study, polymeric nanoparticles were utilized to co-deliver a water-soluble CDDP derivative, poly (γ, L-glutamic acid)-CDDP conjugate, and a naturally occurring compound derived from broccoli, sulforaphane, which can achieve efficient glutathione (GSH) depletion, to enhance the accumulation of CDDP in cancer cells. Results show that compared with combinational treatment of CDDP and SFN, the nanoparticles were more effectively internalized and could significantly reduce GSH content in breast cancer cells, leading to a notable increase in DNA-bound Pt and DNA damage-induced apoptosis. Moreover, in an orthotopic breast cancer model, the nanoparticles achieved a significantly higher tumor accumulation and exhibited a more powerful anti-tumor activity. Finally, this nano-enhanced chemotherapy was further confirmed in a liver cancer model with high-expression of GSH. Taken together, this sulforaphane-based nano-strategy holds great promise to enhance the sensitivity and therapeutic efficacy of Pt-based chemotherapy.

Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl i...

Excess iron deposition in the brain often causes oxidative stress-related damage and necrosis of dopaminergic neurons in the substantia nigra and has been reported to be one of the major vulnerability factors in Parkinson's disease (PD). Iron chelation therapy using deferoxamine (DFO) may inhibit this nigrostriatal degeneration and prevent the progress of PD. However, DFO shows very short half-life in vivo and hardly penetrates the blood brain barrier (BBB). Hence, it is of great interest to develop DFO formulations for safe and efficient intracerebral drug delivery. Herein, we report a polymeric nanoparticle system modified with brain-targeting peptide rabies virus glycoprotein (RVG) 29 that can intracerebrally deliver DFO. The nanoparticle system penetrates the BBB possibly through specific receptor-mediated endocytosis triggered by the RVG29 peptide. Administration of these nanoparticles significantly decreased iron content and oxidative stress levels in the substantia nigra and striatum of PD mice and effectively reduced their dopaminergic neuron damage and as reversed their neurobehavioral deficits, without causing any overt adverse effects in the brain or other organs. This DFO-based nanoformulation holds great promise for delivery of DFO into the brain and for realizing iron chelation therapy in PD treatment.

Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2. Due to the specific endocytic uptake mechanism of nanocarriers and gene-silencing effect of RRM2 siRNA, this nanomedicine formulation significantly increased GEM chemosensitivity in tumor models of genetically engineered Panc1 cells with low hENT1 or high RRM2 expression. Moreover, in a series of patient-derived cancer cells, we demonstrated that the therapeutic benefits of the nanomedicine formulations were associated with the expression levels of hENT1 and RRM2. In summary, we found that the essential factors of GEM chemosensitivity were the expression levels of hENT1 and RRM2, and synthesized nanoformulations can overcome these problems. This unique design of nanomedicine not only provides a universal platform to enhance chemosensitivity but also contributes to the precision design and personalized treatment in nanomedicine.

Although postsurgical chemotherapy is frequently used for the treatment of breast cancer, tumor recurrence is still a frequent event. Enhancing the efficacy of chemotherapy via localized drug delivery may help to prevent breast cancer recurrence. To achieve this goal, we designed a hydrogel nanocarrier that could be injected at the tumor site by coassembly of tailor-made hexapeptide and doxorubicin. Evidently, on the basis of our findings, the sustained release of drug from the hydrogel led to a reduction in cancer recurrence, including the suppression of primary regrowth and distant metastasis. This localized chemotherapy strategy did not show any obvious side effects in vivo and represents a promising adjuvant therapeutic strategy for breast cancer recurrence.

Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.

Cysteine-based chiral optically active carbon dots (CDs) and their effects on cellular energy metabolism, which is vital for essential cellular functions, have been barely reported. A green and effective synthesis strategy for chiral N-S-doped CDs (fluorescence quantum yield ca. 41.26 %) based on hydrothermal treatment of l- or d-cysteine at as low as 60 °C has been developed. This suggested that cysteine was instable in aqueous solutions and acts as a warning for high-temperature synthesis of nanomaterials using cysteine as stabilizer. Human bladder cancer T24 cells treated with l-CDs showed up-regulated glycolysis, while d-CDs had no similar effects. In contrast, no disturbance to the basal mitochondrial aerobic respiration of T24 cells was caused by either chiral CD.

As a potent autophagy inducer, Beclin 1 is essential for the initiation of autophagic cell death, and triggering extensive autophagy by targeted delivery of Beclin 1 to tumors has enormous potential to inhibit tumor growth. Yet, the therapeutic application of Beclin 1 is hampered by its inability to internalize into cells and nonselective biodistribution in vivo. To tackle this challenge, we employed a novel Beclin 1 delivery manner by constructing a functional protein (Trx-pHLIP-Beclin 1, TpB) composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), and an evolutionarily conserved motif of Beclin 1. This protein could effectively transport Beclin 1 to breast and ovarian cancer cell lines under weakly acidic conditions (pH 6.5), markedly inhibit tumor cell growth and proliferation, and induce obvious autophagy. Furthermore, the in vivo antitumor efficacy of the functional Beclin 1 against an SKOV3 xenograft tumor mouse model was tested via intravenous injection. TpB preferentially accumulated in tumors and exhibited a significantly higher tumor growth inhibition than the nontargeted Beclin 1 control, whereas no overt side effects were observed. Taken together, this study sheds light on the potential application of TpB as a highly efficient yet safe antitumor agent for cancer treatment.

Aerobic glycolysis enables cancer cells to rapidly take up nutrients (e.g., nucleotides, amino acids, and lipids) and incorporate them into the biomass needed to produce a new cell. In contrast to existing chemotherapy/radiotherapy strategies, inhibiting aerobic glycolysis to limit the adenosine 5′-triphosphate (ATP) yield is a highly efficient approach for suppressing tumor cell proliferation. However, most, if not all, current inhibitors of aerobic glycolysis cause significant adverse effects because of their nonspecific delivery and distribution to nondiseased organs, low bioavailability, and a narrow therapeutic window. New strategies to enhance the biosafety and efficacy of these inhibitors are needed for moving them into clinical applications. To address this need, we developed a liposomal nanocarrier functionalized with a well-validated tumor-targeting peptide to specifically deliver the aerobic glycolysis inhibitor 3-bromopyruvate (3-BP) into the tumor tissue. The nanoparticles effectively targeted tumors after systemic administration into tumor-bearing mice and suppressed tumor growth by locally releasing 3-BP to inhibit the ATP production of the tumor cells. No overt side effects were observed in the major organs. This report demonstrates the potential utility of the nanoparticle-enabled delivery of an aerobic glycolysis inhibitor as an anticancer therapeutic agent.

Congenital dyserythropoietic anaemias (CDAs) are a group of rare haematological disorders characterized by ineffective erythropoiesis and dyserythropoiesis and reduced numbers of red cells, often with an abnormal morphology. Pathogenic defects in CDAN1 , C15ORF41 , SEC23B , KIF23 , KLF1 and GATA1 genes have been identified in CDAs patients. In this study, we described 13 unrelated Chinese CDAs patients and identified 21 mutations, including 5 novel mutations in CDAN1 gene, and 5 novel mutations in SEC23B gene. Additionally, we predicted the molecular consequence of these missense mutations with Polymorphism Phenotyping v2 (Polyphen), Sorting Intolerant From Tolerant (SIFT), MutPred ( http://mutpred1.mutdb.org /) and Protein Variation Effect Analyzer (Provean, http://provean.jcvi.org/seq_submit.php ) and analyzed the conservation of the mutated amino acid among proteins from several mammalian species.

In this issue of Matter, Liu and co-workers prepared a unique type of radioisotope-labeled, nitric oxide (NO)-releasing nanosheets for effectively relieving hypoxia and immunosuppression in tumor microenvironment, which greatly enhance the efficacy of radiotherapy and immunotherapy.

Biopolymer-based hydrogel beads possessing intrinsic low-toxicity, biocompatibility and biodegradability have gained widespread utility in several applications. Among the biopolymers, cellulose is one of the most abundant renewable biomaterials. Herein cellulose hydrogel beads have been prepared by dissolving cellulose in 68% ZnCl2 solution and then crosslinking the polymer chains through calcium ions. The water and ethanol washing of the beads profoundly influences the beads architecture as characterized by Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray powder diffraction and Scanning electron microscopy. The total crystallinity index of the beads increases with the amount of calcium ions that is further enhanced by water washing. These beads, possessing a layer-like nanoporous structure, are capable of loading bovine serum albumin (BSA) and releasing in a sustained manner. The outcome promises a large-scale production of cellulose beads having the potential to be eco-friendly and inexpensive delivery carriers in food, pharmaceutical, medical and agriculture applications.

Safety analysis of engineered nanomaterials (ENMs) presents a formidable challenge regarding environmental health and safety, due to their complicated and diverse physicochemical properties. Although large amounts of data have been published regarding the potential hazards of these materials, we still lack a comprehensive strategy for their safety assessment, which generates a huge workload in decision-making. Thus, an integrated approach is urgently required by government, industry, academia and all others who deal with the safe implementation of nanomaterials on their way to the marketplace. The rapid emergence and sheer number of new nanomaterials with novel properties demands rapid and high-content screening (HCS), which could be performed on multiple materials to assess their safety and generate large data sets for integrated decision-making. With this approach, we have to consider reducing and replacing the commonly used rodent models, which are expensive, time-consuming, and not amenable to high-throughput screening and analysis. In this review, we present a ‘Library Integration Approach’ for high-content safety analysis relevant to the ENMs. We propose the integration of compositional and property-based ENM libraries for HCS of cells and biologically relevant organisms to be screened for mechanistic biomarkers that can be used to generate data for HCS and decision analysis. This systematic approach integrates the use of material and biological libraries, automated HCS and high-content data analysis to provide predictions about the environmental impact of large numbers of ENMs in various categories. This integrated approach also allows the safer design of ENMs, which is relevant to the implementation of nanotechnology solutions in the pharmaceutical industry.

After centuries of development, using vaccination to stimulate immunity has become an effective method for prevention and treatment of a variety of diseases including infective diseases and cancers. However, the tailor-made efficient delivery system for specific antigens is still urgently needed due to the low immunogenicity and stability of antigens, especially for vaccines to induce CD8+ T cells-mediated cellular immunity. Unlike B cells-mediated humoral immunity, CD8+ T cells-mediated cellular immunity mainly aims at the intracellular antigens from microorganism in virus-infected cells or genetic mutations in tumor cells. Therefore, the vaccines for stimulating CD8+ T cells-mediated cellular immunity should deliver the antigens efficiently into the cytoplasm of antigen presenting cells (APCs) to form major histocompatibility complex I (MHCI)-antigen complex through cross-presentation, followed by activating CD8+ T cells for immune protection and clearance. Importantly, nanotechnology has been emerged as a powerful tool to facilitate these multiple processes specifically, allowing not only enhanced antigen immunogenicity and stability but also APCs-targeted delivery and elevated cross-presentation. This review summarizes the process of CD8+ T cells-mediated cellular immunity induced by vaccines and the technical advantages of nanotechnology implementation in general, then provides an overview of the whole spectrum of nanocarriers studied so far and the recent development of delivery nanotechnology in vaccines against infectious diseases and cancer. Finally, we look forward to the future development of nanotechnology for the next generation of vaccines to induce CD8+ T cells-mediated cellular immunity.

Targeting B7-H3 chimeric antigen receptor (CAR) T cells has antitumor potential for therapy of non-small cell lung cancer (NSCLC) in preclinical studies. However, CAR T cell therapy remains a formidable challenge for the treatment of solid tumors due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Nanozymes exhibit merits modulating the immunosuppression of the tumor milieu. Here, a synergetic strategy by combination of nanozymes and CAR T cells in solid tumors is described. This nanozyme with dual photothermal-nanocatalytic properties is endowed to remodel TME by destroying its compact structure. It is found that the B7-H3 CAR T cells infused in mice engrafted with the NSCLC cells have superior antitumor activity after nanozyme ablation of the tumor. Importantly, it is found that the changes altered immune-hostile cancer environment, resulting in enhanced activation and infiltration of B7-H3 CAR T cells. The first evidence that the process of combination nanozyme therapy effectively improves the therapeutic index of CAR T cells is presented. Thus, this study clearly supports that the TME-immunomodulated nanozyme is a promising tool to improve the therapeutic obstacles of CAR T cells against solid tumors.

The imbalance of gut microbiota, such as dysbiotic expansion of Enterobacteriaceae, is strongly associated with the progress of inflammatory bowel disease (IBD) via exacerbating gut inflammation and disturbing intestinal mucosal barrier. Recently, a microbiota-based strategy is an attractive paradigm for IBD therapy. Here, we explored the therapeutic potential of tungsten oxide nanoparticles (WO3NPs) against DSS-induced acute colitis mice. WO3NPs (47.9 nm in diameter) significantly reduced intestinal inflammation, attenuated bacterial translocation, restored the colonic epithelium barriers, and remodeled gut microbiota homeostasis in inflamed colon, compared with the free tungsten (sodium tungstate). The element quantification and mapping results showed WO3NPs could increase the adherence of tungsten with Enterobacteriaceae in colonic mucus layer, which inhibited Enterobacteriaceae growth by microbial metabolic reprogramming and ameliorate colitis. This nano-enabled approach for tungsten reduced its deposition in the main organ except for the colon thereby improve the therapeutic efficacy with good biosafety. Together, our results provide insights into the potential nanotherapeutics of WO3NPs against the invasion processes of microbiota in the treatment of IBD.

KRAS mutation is the most common genetic event in pancreatic cancer. Whereas KRAS itself has proven difficult to inhibit, agents that target key downstream signals of KRAS, such as RAF, are possibly effective for pancreatic cancer treatment. Because selective BRAF inhibitors paradoxically induce downstream signaling activation, a pan-RAF inhibitor, LY3009120 is a better alternate for KRAS-mutant tumor treatment. Here we explored a new combinational strategy using a YAP inhibitor and LY3009120 in pancreatic cancer treatment. We found that reduced YAP expression closely correlates with longer relapse-free and overall survival of patients. Stable knockdown of YAP significantly inhibited pancreatic cancer cell proliferation and tumor growth. In addition, LY3009120 exhibited a dramatically enhanced antitumor effect in combination with YAP knockdown. YAP depletion blocks the activation of a parallel AKT signal pathway after LY3009120 treatment. Finally, combination with a YAP inhibitor, verteporfin, significantly enhanced the antitumor efficacy of LY3009120. Collectively, our results demonstrate that genetic or pharmacological inhibition of YAP can increase sensitivity to LY3009120 in pancreatic cancer through blocking compensatory activation of a parallel AKT signal pathway, thereby validating a combinatorial approach for treating KRAS-mutant pancreatic cancer.

Pancreatic cancer, one of the leading causes of cancer-related mortality, is characterized by desmoplasia and hypovascular cancerous tissue, with a 5 year survival rate of8%. To overcome the severe resistance of pancreatic cancer to conventional therapies, we synthesized gold nanoshell-coated rod-like mesoporous silica (GNRS) nanoparticles which integrated cascade tumor targeting (mediated by photothermal effect and molecular receptor binding) and photothermal treatment-enhanced gemcitabine chemotherapy, under mild near-infrared laser irradiation condition. GNRS significantly improved gemcitabine penetration and accumulation in tumor tissues, thus destroying the dense stroma barrier of pancreatic cancer and reinforcing chemosensitivity in mice. Our current findings strongly support the notion that further development of this integrated plasmonic photothermal strategy may represent a promising translational nanoformulation for effective treatment of pancreatic cancer with integral cascade tumor targeting strategy and enhanced drug delivery efficacy.

With recent advances in understanding the genomic underpinnings and oncogenic drivers of pathogenesis in different subtypes, it is increasingly clear that proper pretreatment diagnostics are essential for the choice of appropriate treatment options for non-small cell lung cancer (NSCLC). Tumor tissue preservation in optimal cutting temperature (OCT) compound is commonly used in the surgical suite. However, proteins recovered from OCT-embedded specimens pose a challenge for LC-MS/MS experiments, due to the large amounts of polymers present in OCT. Here we present a simple workflow for whole proteome analysis of OCT-embedded NSCLC tissue samples, which involves a simple trichloroacetic acid precipitation step. Comparisons of protein recovery between frozen versus OCT-embedded tissue showed excellent consistency with more than 9200 proteins identified. Using an isobaric labeling strategy, we quantified more than 5400 proteins in tumor versus normal OCT-embedded core needle biopsy samples. Gene ontology analysis indicated that a number of proliferative as well as squamous cell carcinoma (SqCC) marker proteins were overexpressed in the tumor, consistent with the patient's pathology based diagnosis of "poorly differentiated SqCC". Among the most downregulated proteins in the tumor sample, we noted a number of proteins with potential immunomodulatory functions. Finally, interrogation of the aberrantly expressed proteins using a candidate approach and cross-referencing with publicly available databases led to the identification of potential druggable targets in DNA replication and DNA damage repair pathways. We conclude that our approach allows LC-MS/MS proteomic analyses on OCT-embedded lung cancer specimens, opening the way to bring powerful proteomics into the clinic. Graphical Abstract ᅟ.

Selenium is a unique, essential trace element that plays an important role in the antioxidant defense and redox regulation of biological processes. We have reported that novel selenium-containing platinum-based anticancer molecules (EG-Se/Pt) had selective cytotoxicity toward cancer cells. Herein, we found the underlying mechanism of selective cytotoxicity to be closely related to the glutathione antioxidant defense system. Elevated reactive oxygen species (ROS) make cancer cells more vulnerable to further elevation of ROS. EG-Se/Pt can induce abnormal increases in ROS by depletion of glutathione. Consequently, the mitochondrial membrane potential collapses and cytochrome c is released, resulting in cell apoptosis. However, EG-Se/Pt analogues, such as EG-Se/Cu and EG-Se/Ni, did not exhibit glutathione depletion capacity or selective killing activity in our investigation, although they can effectively kill cancer cells. These results suggest that the glutathione antioxidant system is an effective target to enable therapeutic selectivity. The amphiphilic property of the selenium-platinum coordination molecules facilitates their assembly into nanoparticles and prolongs the circulation time of the drug in the bloodstream, which is important for in vivo drug delivery. Our in vivo anticancer study demonstrated that the tumor growth inhibition rate of EG-Se/Pt can reach 69% (

Exosomes, molecular cargos secreted by almost all mammalian cells, are considered as promising biomarkers to identify many diseases including cancers. However, the small size of exosomes (30–200 nm) poses serious challenges in their isolation from complex media containing a variety of extracellular vesicles (EVs) of different sizes, especially in small sample volumes. Here we present a viscoelasticity-based microfluidic system to directly separate exosomes from cell culture media or serum in a continuous, size-dependent, and label-free manner. Using a small amount of biocompatible polymer as the additive in the media to control the viscoelastic forces exerted on EVs, we are able to achieve a high separation purity (>90%) and recovery (>80%) of exosomes. The proposed technique may serve as a versatile platform to facilitate exosome analyses in diverse biochemical applications.

Accumulation and aggregation of β-amyloid (Aβ) peptides result in neuronal death, leading to cognitive dysfunction in Alzheimer's disease. The self-assembled Aβ molecules form various intermediate aggregates including oligomers that are more toxic to neurons than the mature aggregates, including fibrils. Thus, one strategy to alleviate Aβ toxicity is to facilitate the conversion of Aβ intermediates to larger aggregates such as fibrils. In this study, we designed a peptide named A3 that significantly enhanced the formation of amorphous aggregates of Aβ by accelerating the aggregation kinetics. Thioflavin T fluorescence experiments revealed an accelerated aggregation of Aβ monomers, accompanying reduced Aβ cytotoxicity. Transgenic Caenorhabditis elegans over-expressing amyloid precursor protein exhibited paralysis due to the accumulation of Aβ oligomers, and this phenotype was attenuated by feeding the animals with A3 peptide. These findings suggest that the Aβ aggregation-promotion effect can potentially be useful for developing strategies to reduce Aβ toxicity.

The tumor microenvironment participates in all stages of tumor progression and has emerged as a promising therapeutic target for cancer therapy. Rapid progress in the field of molecular self-assembly using various biologic molecules has resulted in the fabrication of nanoformulations that specifically target and regulate microenvironment components to inhibit tumor growth. This inhibition process is based on differentiating between biophysicochemical cues guiding tumor and normal tissue microenvironments. Peptides and peptide derivatives, owing to their biocompatibility, chemical versatility, bioactivity, environmental sensitivity, and biologic recognition abilities, have been widely used as building blocks to construct multifunctional nanostructures for targeted drug delivery and controlled release. Several groups of peptides have been identified as having the ability to penetrate plasma membranes, regulate the essential signaling pathways of angiogenesis and immune reactions, and recognize key components in the tumor microenvironment (such as vascular systems, stromal cells, and abnormal tumor biophysicochemical features). Thus, using different modules, various functional peptides, and their derivatives can be integrated into nanoformulations specifically targeting the tumor microenvironment with increased selectivity, on-demand response, elevated cellular uptake, and improved tumor therapy. In this review, we introduce several groups of functional peptides and highlight peptide-based nanoformulations that specifically target the tumor microenvironment. We also provide our perspective on the development of smart drug-delivery systems with enhanced therapeutic efficacy.

Extensive evidence has shown that platelets support tumor metastatic progression by inducing epithelial-mesenchymal transition of cancer cells and by shielding circulating tumor cells from immune-mediated elimination. Therefore, blocking platelet function represents a potential new avenue for therapy focused on eliminating metastasis. Here we show that liposomal nanoparticles bearing the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) can deliver a platelet inhibitor, ticagrelor, into tumor tissues to specifically inhibit tumor-associated platelets. The drug-loaded nanoparticles (CREKA-Lipo-T) efficiently blocked the platelet-induced acquisition of an invasive phenotype by tumor cells and inhibited platelet-tumor cell interaction in vitro. Intravenously administered CREKA-Lipo-T effectively targeted tumors within 24 h, and inhibited tumor metastasis without overt side effects. Thus, the CREKA-Lipo formulation provides a simple strategy for the efficient delivery of anti-metastatic drugs and shows considerable promise as a platform for novel cancer therapeutics.

Rapid and robust hydrogels are essential in realizing continuous glucose monitoring in diabetes monitoring. However, existing hydrogels are limited in satisfying all of the sensory requirements such as detection range, response time, recoverability and biocompatibility. Here, we have developed a surface-initiated polymerization method to chemically immobilize a nano-boronic acid-hydrogel membrane onto a quartz crystal, then used a quartz crystal microbalance (QCM) to achieve real-time monitoring of glucose. The experimental results show that this hydrogel possesses enhanced binding properties to glucose under physiological conditions (pH 7.0–7.5) and blood glucose concentration (BGC) (1.1–33.3 mM). Moreover, our hydrogel displayed a rapid response time (∼100 s) to glucose, high biocompatibility in vivo through an animal model. The hydrogel has a great potential as a sensitive glucose probe for implantable continuous glucose sensors.

Juvenile hemochromatosis is caused by the defects of HFE2 gene, located on chromosome 1q with clinical manifestations of iron overload and affected organ damage before adulthood. The present study reports a Chinese juvenile hemochromatosis patient with severe iron overload and unique genetic defects. Gene sequencing results revealed a missense mutation (Q6H) and a nonsense mutation (C321X) in the HFE2 gene of the proband and his father, while another missense mutation (E3D) was identified in his mother. In addition, a gross deletion (about 400 kilobasepairs) was demonstrated in the other HFE2 allele of the proband. We conclude that the gross deletion, combined with the two deleterious point mutations, resulted in a severe hemochromatosis phenotype in the patient.

Quercetin (Que) is a natural multifunctional bioflavonoid, and has shown great potential for reducing adverse side effects and enhancing anti-tumor efficacy of chemotherapeutic drugs. However, its clinical application is limited due to very low solubility and structural instability in physiological systems. Herein, we co-delivered hydrophobic quercetin and hydrophilic doxorubicin (Dox) by developing a biocompatible nanocarrier comprising of an amphiphilic polymer, methoxy poly(ethylene glycol) and poly(D, L-lactide-co-glycolide), respectively. The anti-tumor and prophylactic efficacy of this system was evaluated in cellular and animal models. Our findings illustrated that the Dox-Que nanoparticulate formulation protected normal vascular endothelial cells from either free or nanoparticulate doxorubicin-induced cytotoxicity and increased cancer cell death. Compared with free doxorubicin and its nanoformulation, co-delivery of quercetin and doxorubicin using our nanosystem synergistically inhibited tumor growth, while maintaining normal levels of cardiac function indicators in serum and recovering the histopathological damages in heart tissue. This study demonstrates a promising strategy for enhancing anti-cancer drug efficacy and reducing nanoparticulate chemotherapy-induced toxicity on normal tissues.

Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T

Prostate cancer is one of the most common malignant tumors in men, and inhibiting metastasis is a key event but still a major challenge in prostate cancer treatment. Cancer-associated fibroblasts (CAFs) play an important role in prostate tumor metastasis by shaping the malignant tumor microenvironment. Herein, we constructed a CAF-targeting siRNA delivery system by loading the fibroblast activation protein-α (FAP-α) antibody onto the cell-penetrating peptide (CPP)-based nanoparticles, which specifically downregulated C-X-C motif chemokine ligand 12 (CXCL12) expression in CAFs. This regulation generated a series of changes through inactivating CAFs so that the malignant prostate tumor microenvironment was reshaped. The tumor cell invasion, migration, and tumor angiogenesis were significantly inhibited, which all contributed to the suppression of the metastasis of an orthotopic prostate tumor. This tumor microenvironment reshaping strategy

The acquisition of stemness in colorectal cancer (CRC) attributed to the recurrence and metastasis in CRC treatment. Therefore, targeting the stemness of CRC forms a basis for the development of novel therapeutic approaches. However, the pain and systemic side effect from long-term of venipuncture injection remain great challenges to neoplastic treatment. Here, we introduce an oral drug delivery system for sustained release of BMI-1 inhibitor (PTC209) that reverse the stemness of CRC to over-come these obstacles. In this system, nanoparticles modified with hyaluronic acid (HA) showed high-affinity to CD44 / CD168 overexpressed-CRC cells, and efficiently targeted to tumor site in a metastatic orthotropic colon cancer mouse model by oral administration. Significantly, the observed tumor growth inhibition is accompanied by decreased expression of stemness markers in the tumor tissues. Furthermore, HA-NPs-PTC209 also significantly prevented metastasis to the gastrointestinal system, while failing to exhibit acute side effects. In summary, we have developed an orally active, easily synthesized nanomedicine that shows promise for the treatment of colon cancer.

A major challenge in cancer vaccine therapy is the efficient delivery of antigens and adjuvants to stimulate a controlled yet robust tumour-specific T-cell response. Here, we describe a structurally well defined DNA nanodevice vaccine generated by precisely assembling two types of molecular adjuvants and an antigen peptide within the inner cavity of a tubular DNA nanostructure that can be activated in the subcellular environment to trigger T-cell activation and cancer cytotoxicity. The integration of low pH-responsive DNA 'locking strands' outside the nanostructures enables the opening of the vaccine in lysosomes in antigen-presenting cells, exposing adjuvants and antigens to activate a strong immune response. The DNA nanodevice vaccine elicited a potent antigen-specific T-cell response, with subsequent tumour regression in mouse cancer models. Nanodevice vaccination generated long-term T-cell responses that potently protected the mice against tumour rechallenge.

The marked augment of drug-resistance to traditional antibiotics underlines the crying need for novel replaceable antibacterials. Research advances have revealed the considerable sterilization potential of two-dimension graphene-based nanomaterials. Subsequently, two-dimensional nanomaterials beyond graphene (2D NBG) as novel antibacterials have also demonstrated their power for disinfection due to their unique physicochemical properties and good biocompatibility. Therefore, the exploration of antibacterial mechanisms of 2D NBG is vital to manipulate antibacterials for future applications. Herein, we summarize the recent research progress of 2D NBG-based antibacterial agents, starting with a detailed introduction of the relevant antibacterial mechanisms, including direct contact destruction, oxidative stress, photo-induced antibacterial, control drug/metallic ions releasing, and the multi-mode synergistic antibacterial. Then, the effect of the physicochemical properties of 2D NBG on their antibacterial activities is also discussed. Additionally, a summary of the different kinds of 2D NBG is given, such as transition-metal dichalcogenides/oxides, metal-based compounds, nitride-based nanomaterials, black phosphorus, transition metal carbides, and nitrides. Finally, we rationally analyze the current challenges and new perspectives for future study of more effective antibacterial agents. This review not only can help researchers grasp the current status of 2D NBG antibacterials, but also may catalyze breakthroughs in this fast-growing field.

The past decades have witnessed the development of a field dedicated to targeting tumor vasculature for cancer therapy. In contrast to conventional chemotherapeutics that need to penetrate into tumor tissues for killing tumor cells, the agents targeting tumor vascular system have two major advantages: direct contact with vascular endothelial cells or the blood and less possibility to induce drug resistance because of high gene stability of endothelial cells. More specifically, various angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs) that block tumor blood supply to inhibit tumor progression, some of which have been applied clinically, have been described. However, off-target effects and high effective doses limit the utility of these formulations in cancer patients. Thus, new strategies with improved therapeutic efficacy and safety are needed for tumor vessel targeting therapy. With the burgeoning developments in nanotechnology, smart nanotherapeutics now offer unprecedented potential for targeting tumor vasculature. Based on specific structural and functional features of the tumor vasculature, a number of different nanoscale delivery systems have been proposed for cancer therapy. In this Account, we summarize several distinct strategies to modulate tumor vasculature with various smart nanotherapeutics for safe and effective tumor therapy developed by our research programs. Inspired by the blood coagulation cascade, we generated nanoparticle-mediated tumor vessel infarction strategies that selectively block tumor blood supply to starve the tumor to death. By specifically delivering thrombin loaded DNA nanorobots (Nanorobot-Th) into tumor vessels, an intratumoral thrombosis is triggered to induce vascular infarction and, ultimately, tumor necrosis. Mimicking the coagulation cascade, a smart polymeric nanogel achieves permanent and peripheral embolization of liver tumors. Considering the critical role of platelets in maintaining tumor vessel integrity, a hybrid (PLP-D-R) nanoparticle selectively depleting tumor-associated platelets (TAP) to boost tumor vessel permeability was developed for enhancing intratumoral drug accumulation. In addition, benefiting from a better understanding of the molecular and cellular underpinnings of vascular normalization, several tumor acidity responsive nanotherapeutics, encapsulating therapeutic peptides, and small interfering RNA were developed to correct the abnormal features of the tumor vasculature. This made the tumor vessels more efficient for drug delivery. While we are still exploring the mechanisms of action of these novel nanoformulations, we expect that the strategies summarized here will offer a promising platform to design effective next-generation nanotherapeutics against cancer and facilitate the clinical translation of smart nanotherapeutics that target tumor vasculature.

Graphdiyne has attracted much interest from researchers for their potential applications in energy storage, catalysis, and biomedical areas. As one of the derivatives of graphdiyne, graphdiyne quantum dots (GDQDs) may possess superior bioactivity due to active acetylene units. However, the biological application of biocompatible GDQDs have not been reported so far. Herein, GDQDs with uniform size and good crystallization were prepared via a classical solvothermal method. The GDQDs exhibit excitation- and pH-dependent fluorescence emission as well as superior photostability, demonstrating their potential for bioimaging. The GDQDs demonstrate efficient cellular uptake and cell imaging without induction of detectable cytotoxic effects in vitro. Systematical safety evaluation further confirmed good biocompatibility of the GDQDs in vivo. Our study preliminarily validates the application of the GDQDs in biomedicine and encourages more thorough studies for better realizing the potential of GDQDs.

Activated platelets have a high affinity for tumor cells, and consequently, they can protect tumor cells from environmental stress and immune attacks. Therefore, preventing platelet-tumor cell interaction can lead to the elimination of circulating tumor cells via natural killer cells and finally metastasis inhibition. It is also shown that CREKA (Cys-Arg-Glu-Lys-Ala), a tumor-homing pentapeptide, targets fibrin-fibronectin complexes that are found on the tumor stroma and the vessel walls. In this study, we linked CREKA to Ticagrelor, a reversible antagonist of the P2Y12 receptor on platelets. In vitro experiments indicated that CREKA-Ticagrelor could not only inhibit the platelet-induced migration of tumor cells with an invasive phenotype but also prevent tumor-platelet interaction. In vivo antitumor and antimetastasis results of this drug showed that CREKA-Ticagrelor could specifically target the tumor tissues within 24 h post intravenous injection and suppress lung metastasis. Meanwhile, by having this antiplatelet drug targeted, its side effects were minimized, and bleeding risk was decreased. Thus, CREKA-Ticagrelor offers an efficient antimetastatic agent.

Rapid cut-off of blood supply in diseases involving thrombosis is a major cause of morbidity and mortality worldwide. However, the current thrombolysis strategies offer limited results due to the therapeutics' short half-lives, low targeting ability, and unexpected bleeding complications. Inspired by the innate roles of platelets in hemostasis and pathological thrombus, platelet membrane-camouflaged polymeric nanoparticles (nanoplatelets) are developed for targeting delivery of the thrombolytic drug, recombinant tissue plasminogen activator (rt-PA), to local thrombus sites. The tailor-designed nanoplatelets efficiently accumulate at the thrombi in pulmonary embolism and mesenteric arterial thrombosis model mice, eliciting a significantly enhanced thrombolysis activity compared to free rt-PA. In addition, the nanoplatelets exhibit improved therapeutic efficacy over free rt-PA in an ischemic stroke model. Analysis of in vivo coagulation indicators suggests the nanoplatelets might possess a low risk of bleeding complications. The hybrid biomimetic nanoplatelets described offer a promising solution to improve the efficacy and reduce the bleeding risk of thrombolytic therapy in a broad spectrum of thrombosis diseases.

Excessive β-adrenergic stimulation induces cardiac fibrosis and inflammation and eventually leads to heart failure. It remains unclear whether the inflammatory factor and infiltration of macrophages are initiated from cardiac cells or the vascular system. We used 13-nm polyethylene glycol (PEG)-coated gold nanoparticles (GNPs) as size probes because they cannot penetrate normal vascular walls, and we found that over-stimulation of β-adrenoceptors mediates cardiac inflammation and fibrosis by increasing vascular permeability. Stimulation with isoproterenol (ISO, a β-adrenoceptor agonist) induced tissue-specific inflammatory infiltration and fibrosis in the hearts of mice. Consistent with these findings, 13-nm PEG-coated GNP as size probes were also observed to have tissue-specific targeting of the fibrotic heart, indicating over-stimulation of β-adrenoceptors, increased vascular permeability in the heart, and initiated cardiac inflammation and fibrosis.

Within tumors, the coagulation-inducing protein tissue factor (TF), a major initiator of blood coagulation, has been shown to play a critical role in the hematogenous metastasis of tumors, due to its effects on tumor hypercoagulability and on the mediation of interactions between platelets and tumor cells. Targeting tumor-associated TF has therefore great therapeutic potential for antimetastasis therapy and preventing thrombotic complication in cancer patients. Herein, we reported a novel peptide-based nanoparticle that targets delivery and release of small interfering RNA (siRNA) into the tumor site to silence the expression of tumor-associated TF. We showed that suppression of TF expression in tumor cells blocks platelet adhesion surrounding tumor cells in vitro. The downregulation of TF expression in intravenously administered tumor cells (i.e., simulated circulating tumor cells [CTCs]) prevented platelet adhesion around CTCs and decreased CTCs survival in the lung. In a breast cancer mouse model, siRNA-containing nanoparticles efficiently attenuated TF expression in the tumor microenvironment and remarkably reduced the amount of lung metastases in both an experimental lung metastasis model and tumor-bearing mice. What's more, this strategy reversed the hypercoagulable state of the tumor bearing mice by decreasing the generation of thrombin-antithrombin complexes (TAT) and activated platelets, both of which are downstream products of TF. Our study describes a promising approach to combat metastasis and prevent cancer-associated thrombosis, which advances TF as a therapeutic target toward clinic applications.

In the version of the Supplementary Information originally published, in Supplementary Fig. 8a, in the bottom row, the left-most image ('Control') was not the correct image; this has now been replaced.

Combining informative imaging methodologies with effective treatments to destroy tumors is of great importance for oncotherapy. Versatile nanotheranostic agents that inherently possess both diagnostic imaging and therapeutic capabilities are highly desirable to meet these requirements. Here, a simple but powerful nanoplatform based on polydopamine-coated gold nanostar (GNS@PDA), which can be easily diversified to achieve various function extensions, is designed to realize functional and anatomical imaging-guided photothermal oncotherapy. This nanoplatform intrinsically enables computed tomography/photoacoustic/two-photon luminescence/infrared thermal tetramodal imaging and can further incorporate fibroblast activation protein (FAP, a protease highly expressed in most of tumors) activatable near-infrared fluorescence imaging and Fe3+-based magnetic resonance imaging for comprehensive diagnosis. Moreover, GNS@PDA exhibits excellent photothermal performance and efficient tumor accumulation. Under the precise...

Rapidly growing cancer cells exhibit a strong dependence on iron for their survival. Thus, iron-removing drugs, iron chelators, have potential applications in cancer treatment. Deferoxamine (DFO) is an efficient iron chelator, but its short circulation half-life and ability to induce hypoxia-inducible factor 1α (HIF1α) overexpression restricts its use as an antitumor agent. In the present study, we first found that a pattern of iron-related protein expression favoring higher intracellular iron closely correlates with shorter overall and relapse-free survival in pancreatic cancer patients. We subsequently found that a combination of DFO and the HIF1α inhibitor, lificiguat (also named YC1), significantly enhanced the antitumor efficacy of DFO in vitro. We then employed transferrin receptor 1 (TFR1) targeting liposomes to codeliver DFO and YC1 to pancreatic tumors in a mouse model. The encapsulation of DFO prolonged its circulation time, improved its accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect, and facilitated efficient uptake by cancer cells, which express high level of TFR1. After entering the tumor cells, the encapsulated DFO and YC1 were released to elicit a synergistic antitumor effect in subcutaneous and orthotopic pancreatic cancer xenografts. In summary, our work overcame two major obstacles in DFO-based cancer treatment through a simple liposome-based drug delivery system. This nanoencapsulation and targeting paradigm lays the foundation for future application of iron chelation in cancer therapy.

Background and Aim: Human SLFN11 gene encodes a protein with structural similarity to RNA helicases, which was reported to sensitize cancer cells to DNA-damaging agents. This study explored the epigenetic regulation and mechanism of SLFN11 in human gastric cancer. Methods: Eight human gastric cancer cell lines and 201 cases of primary gastric cancer were analyzed. Methylation specific PCR, flow cytometry, xenograft mouse model and siRNA technique were employed. Results: SLFN11 was methylated in 29.9% (60/201) of primary gastric cancer. The expression of SLFN11 was regulated by promoter region methylation. Methylation of SLFN11 was significantly associated with tumor size (p < 0.05). SLFN11 suppressed gastric cancer growth both in vitro and in vivo and enhanced the ability of cisplatin to induce S-phrase arrest and apoptosis in gastric cancer cells. Conclusions: SLFN11 is frequently methylated in human gastric cancer, and its expression is regulated by promoter region methylation. Our results demonstrate that SLFN11 is a tumor suppressor in human gastric cancer, and methylation of SLFN11 may serve as a cisplatin resistant marker in human gastric cancer.

Photodynamic therapy (PDT) is a promising anticancer treatment and is clinically approved for different types of tumors. However, current PDT suffers several obstacles, including its neutralization by excess glutathione (GSH) in the tumor tissue and its strongly proangiogenic tumor response. In this work, a biomimic, multifunctional nanoparticle-based PDT agent, combining a tumor-targeted photosensitizer with GSH scavenging and antiangiogenesis therapy, is developed. A porphyrinic Zr-metal-organic framework nanoparticle is used simultaneously as the photosensitizer and the delivery vehicle of vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor apatinib. The core nanoparticles are wrapped in MnO2 to consume the intratumoral GSH and then decorated with a tumor cell membrane camouflage. After intravenous administration, the nanoparticles selectively accumulate in tumor through homotypic targeting mediated by the biomimic decoration, and the combination of enhanced PDT and antiangiogenic drug significantly improves their tumor inhibition efficiency. This study provides an integrated solution for mechanism-based enhancement of PDT and demonstrates the encouraging potential for multifunctional nanosystem applicable for tumor therapy.

Pharmaceutical uses of cancer therapeutics, such as intravenous thrombin to elicit blood coagulation, have been hampered by lack of tumor specificity. Based on rapid progress in DNA origami-based machines capable of transporting molecular payloads, DNA nanorobots have been constructed to specifically deliver therapeutic agents into tumor vessels.

Pancreatic cancer (PCa) is one of the most lethal malignancies, with a 5 year survival rate of less than 8%. Current treatment regiments have a low response rate in unselected patients. However, the subgroup of PCa patients with BRCA mutations may benefit from poly-ADP-ribose polymerase inhibitors (PARPi) due to their biological properties in DNA repair. Dose-limiting toxicity in normal tissues is frequently observed when PARPi are combined with other chemotherapies, and the co-delivery of two drugs to tumor sites at an adequate concentration is challenging. To address this issue, we have engineered an epidermal growth factor receptor (EGFR) targeting (with GE11 peptide) self-assembly amphiphilic peptide nanoparticle (GENP) to co-deliver gemcitabine and the PARPi olaparib to treat BRCA mutant PCa. The GENP was relatively stable, exhibited high encapsulation efficiency, and could coordinately release the two drugs in tumor milieu. Gemcitabine and olaparib showed strong synergistic actions in optimized conditions in vitro. The nanoparticle prolonged the half-life of both drugs and resulted in their tumor accumulation at the optimal therapeutic ratio in vivo. The drug-loaded nanoparticles were able to significantly suppress tumor growth in a murine PCa model with minimal side effects. Drug co-delivery of DNA damaging agents and PARP inhibitors via the GENP represents a promising approach for treatment of pancreatic cancers with molecular defects in the DNA repair pathway.