Phospholipid peroxidation in macrophage confers tumor resistance by suppressing phagocytic capability towards ferroptotic cells.

Ferroptosis holds significant potential for application in cancer therapy. However, ferroptosis inducers are not cell-specific and can cause phospholipid peroxidation in both tumor and non-tumor cells. This limitation greatly restricts the use of ferroptosis therapy as a safe and effective anticancer strategy. Our previous study demonstrated that macrophages can engulf ferroptotic cells through Toll-like receptor 2 (TLR2). Despite this advancement, the precise mechanism by which phospholipid peroxidation in macrophages affects their phagocytotic capability during treatment of tumors with ferroptotic agents is still unknown. Here, we utilized flow sorting combined with redox phospholipidomics to determine that phospholipid peroxidation in tumor microenvironment (TME) macrophages impaired the macrophages ability to eliminate ferroptotic tumor cells by phagocytosis, ultimately fostering tumor resistance to ferroptosis therapy. Mechanistically, the accumulation of phospholipid peroxidation in the macrophage endoplasmic reticulum (ER) repressed TLR2 trafficking to the plasma membrane and caused its retention in the ER by disrupting the interaction between TLR2 and its chaperone CNPY3. Subsequently, this ER-retained TLR2 recruited E3 ligase MARCH6 and initiated the proteasome-dependent degradation. Using redox phospholipidomics, we identified 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) as the crucial mediator of these effects. Conclusively, our discovery elucidates a novel molecular mechanism underlying macrophage phospholipid peroxidation-induced tumor resistance to ferroptosis therapy and highlights the TLR2-MARCH6 axis as a potential therapeutic target for cancer therapy.

Boosting anaerobic digestion of long chain fatty acid with microbial electrolysis cell combining metal organic framework as cathode: Biofilm construction and metabolic pathways.

The role of metal organic framework (MOF) modified cathode in promoting long chain fatty acid (LCFA) methanation was identified in microbial electrolysis cell coupled anaerobic digestion (MEC-AD) system. The maximum methane production rate of MEC-AD-MOF achieved 49.8 ± 3.4 mL/d, which increased by 41 % compared to MEC-AD-C. The analysis of bio-cathode biofilm revealed that microbial activity, distribution, population, and protein secretion prompted by MOF cathode, which in turn led to an acceleration of electron transfer between the cathode and microbes. Specifically, the relative abundance of acetate-oxidizing bacterium (Mesotoga) in MEC-AD-MOF was 1.5-3.6 times higher than that in MEC-AD-C, with a co-metabolized enrichment of Methanobacterium. Moreover, MOF cathode reinforced LCFA methanation by raising the relative abundance of genes coded key enzymes involved in CO2-reducing pathway, and elevating the tolerance of microbes to LCFA inhibition. These results indicate that MOF can enhance biofilm construction in MEC-AD, thereby improving the treatment performance of lipid wastewater.

A ferroptosis-targeting ceria anchored halloysite as orally drug delivery system for radiation colitis therapy.

Radiation colitis is the leading cause of diarrhea and hematochezia in pelvic radiotherapy patients. This work advances the pathogenesis of radiation colitis from the perspective of ferroptosis. An oral Pickering emulsion is stabilized with halloysite clay nanotubes to alleviate radiation colitis by inhibiting ferroptosis. Ceria nanozyme grown in situ on nanotubes can scavenge reactive oxygen species, and deferiprone was loaded into the lumen of nanotubes to relieve iron stress. These two strategies effectively inhibit lipid peroxidation and rescue ferroptosis in the intestinal microenvironment. The clay nanotubes play a critical role as either a medicine to alleviate colitis, a nanocarrier that targets the inflamed colon by electrostatic adsorption, or an interfacial stabilizer for emulsions. This ferroptosis-based strategy was effective in vitro and in vivo, providing a prospective candidate for radiotherapy protection via rational regulation of specific oxidative stress.

Non-spherical assemblies of chitin nanocrystals by drop impact assembly.

Preparing complex non-spherical assemblies of elongated nanoparticles and exploring their topological conformations is a challenge due to liquid crystals' mobility and elastic distortion. Here, we fabricated a variety of non-spherical liquid crystal assemblies of chitin nanocrystals (ChNCs) in a coagulation bath containing sodium triphosphate (STP) by drop impact assembly method, and the forming mechanism and internal topology were systematically investigated. The collection height, ChNCs concentration, and STP concentration have significant influence on the shape and size of the assembled structures. Long-range ordered structures and long-lived topological textures of the ChNCs liquid crystal can be obtained since a molecular interaction of hydrogen bonding and electrostatic attractions between ChNCs and STP occur during the impact assembly. Rheological and kinetic analysis suggested the shear thinning behavior of the ChNCs liquid crystals and the rapid gelation phenomenon of ChNCs induced by STP. Morphology results showed that the rod-like ChNCs in the non-spherical assemblies were orderly and closely arranged with periodic repetition and layered structure. The non-spherical assemblies of ChNCs liquid crystals can be used as carriers of carbon nanotubes, magnetic Fe3O4 nanoparticles, synthesized polymers, and anticancer drugs for functional composite applications. The drop impact assembly method of ChNCs liquid crystal structure is highly controllable on the composition, morphology, and function, which shows promising applications in energy, environmental-friendly, and bioactive materials.

Highly Elastic and Anisotropic Wood-Derived Composite Scaffold with Antibacterial and Angiogenic Activities for Bone Repair.

Scaffold-based tissue engineering is a promising strategy to address the rapidly growing demand for bone implants, but developing scaffolds with bone extracellular matrix-like structures, suitable mechanical properties, and multiple biological activities remains a huge challenge. Here, it is aimed to develop a wood-derived composite scaffold with an anisotropic porous structure, high elasticity, and good antibacterial, osteogenic, and angiogenic activities. First, natural wood is treated with an alkaline solution to obtain a wood-derived scaffold with an oriented cellulose skeleton and high elasticity, which can not only simulate collagen fiber skeleton in bone tissue but also greatly improve the convenience of clinical implantation. Subsequently, chitosan quaternary ammonium salt (CQS) and dimethyloxalylglycine (DMOG) are further modified on the wood-derived elastic scaffold through a polydopamine layer. Among them, CQS endows the scaffold with good antibacterial activity, while DMOG significantly improves the scaffold's osteogenic and angiogenic activities. Interestingly, the mechanical characteristics of the scaffolds and the modified DMOG can synergistically enhance the expression of yes-associated protein/transcriptional co-activator with PDZ binding motif signaling pathway, thereby effectively promoting osteogenic differentiation. Therefore, this wood-derived composite scaffold is expected to have potential application in the treatment of bone defects.

Sustainable, High-Performance, and Biodegradable Plastics Made from Chitin.

A high-performance biodegradable plastic was made from a chitin KOH/urea solution. The solution was transferred into a hydrogel by cross-linking using epichlorohydrin and ethanol immersion, and a chitin bioplastic was finally prepared by drying in a mold at 40 °C. The solution concentration positively impacts viscosity, crystallinity, and smoothness. A 4% chitin bioplastic exhibits high barrier properties, flame retardancy, high-temperature resistance, mechanical properties (tensile strength up to 107.1 MPa), and soil degradation properties. The chitin bioplastic can be completely degraded by microorganisms in 7 weeks. In addition, biosafety tests suggest that chitin is safe for cells and crops (wheat and mung beans). The chitin bioplastic was further applied to containers, straws, cups, and photoprotection, and it was found that the water resistance and transparency were comparable to those of commercial polypropylene plastics. Due to the excellent performance, safety, and sustainability of the chitin bioplastic, it is expected to become a good substitute for conventional fossil fuel-based plastics.

Dual-Cross-linked Liquid Crystal Hydrogels with Controllable Viscoelasticity for Regulating Cell Behaviors.

The liquid crystal properties and viscoelasticity of the natural bone extracellular matrix (ECM) play a decisive role in guiding cell behavior, conducting cell signals, and regulating mineralization. Here, we develop a facile approach for preparing a novel polysaccharide hydrogel with liquid crystal properties and viscoelasticity similar to those of natural bone ECM. First, a series of chitin whisker/chitosan (CHW/CS) hydrogels were prepared by chemical cross-linking with genipin, in which CHW can self-assemble to form cholesteric liquid crystals under ultrasonic treatment and CS chains can enter into the gaps between the helical layers of the CHW cholesteric liquid crystal phase to endow morphological stability and good mechanical properties. Subsequently, the obtained chemically cross-linked liquid crystal hydrogels were immersed into the desired concentration of the NaCl solution to form physical cross-linking. Due to the Hofmeister effect, the as-prepared dual-cross-linked liquid crystal hydrogels showed an enhanced modulus, viscoelasticity similar to that of natural ECM with relatively fast stress relaxation behavior, and fold surface morphology. Compared to both CHW/CS hydrogels without liquid crystal properties and CHW/CS liquid crystal hydrogels without further physical cross-linking, the dual-cross-linked CHW/CS liquid crystal hydrogels are more favorable for the adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells. This approach could inspire the design of hydrogels mimicking the liquid crystal properties and viscoelasticity of natural bone ECM for bone repair.

Cell Membrane-Coated Halloysite Nanotubes for Target-Specific Nanocarrier for Cancer Phototherapy.

Naturally-occurring halloysite nanotubes (HNTs) have many advantages for constructing target-specific delivery of phototherapeutic agents. Here, HNTs were labeled with fluorescein isothiocyanate (FITC) and loaded with the type-II photosensitizer indocyanine green (ICG) for phototherapy. HNTs-FITC-ICG was structurally stable due to presence of HNTs as the nanocarrier and protective agent. The nanocarrier was further wrapped with red blood cell membrane (RBCM) to enhance the biocompatibility. The HNTs-FITC-ICG-RBCM nanocarrier show high cytocompatibility and hemocompatibility. Due to the photothermal effect of ICG, a significant temperature rising was achieved by irradiation of the nanocarrier using 808 nm laser. The photothermal temperature rising was used to kill the cancer cells effectively. The HNTs-FITC-ICG-RBCM nanocarrier was further linked with anti-EpCAM to endow it with targeting therapy performance against breast cancer, and the anti-EpCAM-conjugated nanocarrier exhibited significantly tumor-specific accumulation. The RBCM-coated and biocompatible HNTs nanocarrier is a promising candidate for target-specific therapy of cancer.

SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling.

Dysfunction of the Hippo pathway enables cells to evade contact inhibition and provides advantages for cancerous overgrowth. However, for a significant portion of human cancer, how Hippo signaling is perturbed remains unknown. To answer this question, we performed a genome-wide screening for genes that affect the Hippo pathway in Drosophila and cross-referenced the hit genes with human cancer genome. In our screen, Prosap was identified as a novel regulator of the Hippo pathway that potently affects tissue growth. Interestingly, a mammalian homolog of Prosap, SHANK2, is the most frequently amplified gene on 11q13, a major tumor amplicon in human cancer. Gene amplification profile in this 11q13 amplicon clearly indicates selective pressure for SHANK2 amplification. More importantly, across the human cancer genome, SHANK2 is the most frequently amplified gene that is not located within the Myc amplicon. Further studies in multiple human cell lines confirmed that SHANK2 overexpression causes deregulation of Hippo signaling through competitive binding for a LATS1 activator, and as a potential oncogene, SHANK2 promotes cellular transformation and tumor formation in vivo. In cancer cell lines with deregulated Hippo pathway, depletion of SHANK2 restores Hippo signaling and ceases cellular proliferation. Taken together, these results suggest that SHANK2 is an evolutionarily conserved Hippo pathway regulator, commonly amplified in human cancer and potently promotes cancer. Our study for the first time illustrated oncogenic function of SHANK2, one of the most frequently amplified gene in human cancer. Furthermore, given that in normal adult tissues, SHANK2's expression is largely restricted to the nervous system, SHANK2 may represent an interesting target for anticancer therapy.

Defining relative mutational difficulty to understand cancer formation.

Most mutations in human cancer are low-frequency missense mutations, whose functional status remains hard to predict. Here, we show that depending on the type of nucleotide change and the surrounding sequences, the tendency to generate each type of nucleotide mutations varies greatly, even by several hundred folds. Therefore, a cancer-promoting mutation may appear only in a small number of cancer cases, if the underlying nucleotide change is too difficult to generate. We propose a method that integrates both the original mutation counts and their relative mutational difficulty. Using this method, we can accurately predict the functionality of hundreds of low-frequency missense mutations in p53, PTEN, and INK4A. Many loss-of-function p53 mutations with dominant negative effects were identified, and the functional importance of several regions in p53 structure were highlighted by this analysis. Our study not only established relative mutational difficulties for different types of mutations in human cancer, but also showed that by incorporating such a parameter, we can bring new angles to understanding cancer formation.

Multifunctional HNT@Fe3O4@PPy@DOX Nanoplatform for Effective Chemo-Photothermal Combination Therapy of Breast Cancer with MR Imaging.

Multifunctional nanoparticles for imaging and treatment in cancer are getting more and more attention recently. Herein, halloysite nanotubes (HNTs), natural clay nanotubes, are designed as multifunctional nanoplatform for targeted delivering photothermal therapy agents and chemotherapeutic drugs. Fe3O4 was anchored on the outer surfaces of HNTs and then doxorubicin (DOX) was loaded on the nanotubes. Afterward, a layer of polypyrrole (PPy), as photothermal agent, was wrapped on the tubes. The nanoplatform of HNT@Fe3O4@PPy@DOX can be guided to tumor tissue by an external magnetic field, and then performs chemo-photothermal combined therapy by 808 nm laser irradiation. HNT@Fe3O4@PPy@DOX shows the ability of T2-weighted magnetic resonance imaging, which could be considered as a promising application in magnetic targeting tumor therapy. In vitro and in vivo experiments demonstrate that HNTs nanoplatform has good biocompatibility and produces a strong antitumor effect trigged by near-infrared laser irradiation. The novel chemo-photothermal therapy nanoplatform based on HNTs may be developed as a multifunctional nanoparticle for imaging and therapy in breast cancer.

Self-assembled structures of halloysite nanotubes: towards the development of high-performance biomedical materials.

Halloysite nanotubes (HNTs), 1D natural tubular nanoparticles, exhibit a high aspect ratio, empty lumen, high adsorption ability, good biocompatibility, and high biosafety, which have attracted researchers' attention in applications of the biomedical area. HNTs can be readily dispersed in water due to their negatively charged surface and good hydrophilicity. The unique rod-like structure and surface properties give HNTs assembly ability into ordered hierarchical structures. In this review, the self-assembly approaches of HNTs including evaporation induced self-assembly by a "coffee-ring" mechanism, shear force induced self-assembly, and electric field force induced self-assembly were introduced. In addition, HNT self-assembly on polymeric substrates and biological substrates including hair, cells, and zebrafish embryos was discussed. These assembly processes are related to noncovalent interactions such as electrostatic, hydrogen bonding, and van der Waals forces or electron-transfer reactions. Moreover, the applications of self-assembled HNT patterns in biomedical areas such as capture of circulating tumor cells, guiding oriented cell growth, controlling cell germination, and delivery of drugs or nutrients were discussed and highlighted. Finally, challenges and future directions of assembly of HNTs were introduced. This review will inspire researchers in the design and fabrication of functional biodevices based on HNTs for tissue engineering, cancer diagnosis/therapy, and personal healthcare products.

Superhydrophobic Polyurethane Foam Coated with Polysiloxane-Modified Clay Nanotubes for Efficient and Recyclable Oil Absorption.

Superhydrophobic polyurethane foam (PUF) is prepared by surface coating of halloysite nanotubes. The nanotubes were first modified by surface grafting with hexadecyltrimethoxysilane, followed by assembly on the PUF by dip coating. This treatment makes the water contact angle of the modified PUF higher than 150°. The modified foam has a highly selective absorption of oils and organic solvents. The absorption ratios of the modified PUF for chloroform and dichloroethane reached 104 and 74, respectively. Such superhydrophobic foam can maintain the oil absorption performance even after 10 absorption-squeezing cycles, demonstrating good recyclability. The modified foam can pick up oil or organic solvent continuously and quickly from water's surface. This hydrophobic nanotube coating also enhances the flame retardancy of the PUF, and the modified foam will extinguish itself maintaining its integrity. The preparation method for hydrophobic and flame-retardant PUF by coating with natural clay nanotubes is a simple process and promises scalable applications in oil-water separation.

Systematic Analysis of Drug Vulnerabilities Conferred by Tumor Suppressor Loss.

In addition to oncogene inhibition, targeting tumor suppressor deficiency could provide potential venues for precision cancer medicine. However, the full spectrum of drug vulnerability conferred by tumor suppressor loss remains unclear. We systematically analyzed how loss of 59 common tumor suppressors each affected cellular sensitivity to 26 different types of anticancer therapeutics. The experiments were performed in a one-gene, one-drug manner, and through such a large gene-drug iteration study, we were able to generate a drug sensitivity map that describes numerous examples of drug resistance or hypersensitivity conferred by tumor suppressor loss. We further delineated the mechanisms of several gene-drug interactions, showing that loss of tumor suppressors could modify drug sensitivity at various steps of drug action. This systematic drug sensitivity map highlights potential drug vulnerabilities associated with tumor suppressor loss, which may help expand precision cancer medicine on the basis of tumor suppressor status.

Clay Nanotubes Aligned with Shear Forces for Mesenchymal Stem Cell Patterning.

Aligned halloysite nanotubes on solid substrates are fabricated by a shearing method with brush assistance. These clay nanotubes are aligned by shear force in strip-like patterns accomplished with drying ordering at elevated temperatures. The nanotubes' orientation is governed by "coffee-ring" formation mechanisms depending on the dispersion concentration, nanotube charge, and speed of thermos-evaporation. Polarized light irradiated through the patterns demonstrates birefringence and confirms the orientation. Scanning electron microscopy and atomic force microscopy show that the nanotubes are aligned along the direction of the wetting lines above 4 wt%, while they are not oriented at lower concentrations. Halloysite concentration, drying temperature, and type of brush fibers affect the pattern ordering. The aligned halloysite systems on glass, tissue culture plates, and polymer films, provide a promising platform for biocell guiding. Human foreskin fibroblasts proliferated well on the aligned clay patterns and the cell orientation agrees with the nanotube direction. Human bone mesenchymal stem cells (HBMSCs) are also cultured on the organized halloysite coating. The clay patterns support HBMSC proliferation with alignment, and such nanostructured substrates promote osteogenesis differentiation without growth factors. This facile method for preparing aligned halloysite patterns on solid substrates is very promising for surface modification in biotissue engineering.

Hydrophobically modified chitin/halloysite nanotubes composite sponges for high efficiency oil-water separation.

A high-performance oil-water separation device that built by environment-friendly materials is a promising strategy to solve water pollution problem. In this study, we developed an oil-water separation system with chitin/halloysite nanotubes (C/HNTs) composites. C/HNTs were crosslinked by epichlorohydrin and freeze-dried, then a porous sponge was formed. The C/HNTs sponge was modified to be hydrophobic via immersing into bromohexadecane ethanol solution. The surface structure, mechanical properties, microstructure, oil absorption and oil-water separation ability of the C/HNTs sponge were investigated. The addition of HNTs significantly increased the compressive strength of chitin sponge without influence on porous structure. IR spectra indicated the successful coating of bromohexadecane on the C/HNTs sponge surface, which enabled the hydrophobicity and lipophilicity of this construct. The inside construct of the C/HNTs sponges were full of interconnected pores, and the pore size ranged from 250 to 500 µm. The absorption capability for various oil and grease were measured, including methylbenzene, sunflower seed oil, carbon dichloride, n-hexane, chloroform and acetone. It is found that the total amount of chloroform absorbed by a C/HNTs sponge was ~11.23 times of the sponge's weight, and the absorption for hexane was ~3.94 times of the sponge's weight. The sponge also exhibited an excellent oil-water separation ability with as high as 98.7% separation efficiency. All the results suggested that the chitin/HNTs sponges with improved mechanical property would have a great potential in oil-water separation.

Rod in Tube: A Novel Nanoplatform for Highly Effective Chemo-Photothermal Combination Therapy toward Breast Cancer.

Gold nanorods (GNRs) and doxorubicin (DOX) were loaded into the lumen of halloysite nanotubes (HNTs) via a rapid synthesis process (2 min) and physical adsorption. The targeting molecules of folic acid (FA) are then conjugated to HNTs via reactions with bovine serum albumin (BSA). The formation of GNRs in HNTs was verified by different techniques. Au-HNT-DOX@BSA-FA shows a maximum temperature of 26.8 °C rising after 8 min of 808 nm laser irradiation under 0.8 W cm-2. The functionalized HNTs exhibited stronger chemotherapeutic effect under laser irradiation as the laser could promote the release of DOX and temperature rising. Au-HNT-DOX@BSA-FA-treated MCF-7 cells exhibited a survival rate of 7.4% after laser irradiation. Au-HNT-DOX@BSA-FA treatment does not induce obvious toxicity in blood biochemistry, liver, and kidney function in normal mice. In vivo chemo-photothermal treatment toward 4T1-bearing mice suggested that Au-HNT-DOX@BSA-FA exhibited remarkable tumor-targeted efficiency and good controlled release effect for DOX. Also, the nanoparticles exhibited a rapid photothermal performance and an ability to inhibit the growth of tumors. Because of the synergistic effect of chemical-photothermal therapy, the toxicity of DOX to normal tissues was reduced on the premise of ensuring the same curative effect with a low dosage of 0.32 mg kg-1. This novel chemo-photothermal therapy nanoplatform provided a safe, rapid, effective, and cheap choice for the treatment of breast tumors both in vitro and in vivo.

Tubule Nanoclay-Organic Heterostructures for Biomedical Applications.

Natural halloysite nanotubes (HNTs) show unique hollow structure, high aspect ratio and adsorption ability, good biocompatibility, and low toxicity, which allow for various biomedical applications in the diagnosis and treatment of diseases. Here, advances in self-assembly of halloysite for cell capturing and bacterial proliferation, coating on biological surfaces and related drug delivery, bone regeneration, bioscaffolds, and cell labeling are summarized. The in vivo toxicity of these clay nanotubes is discussed. Halloysite allows for 10-20% drug loading and can extend the delivery time to 10-100 h. These drug-loaded nanotubes are doped into the polymer scaffolds to release the loaded drugs. The rough surfaces fabricated by self-assembly of the clay nanotubes enhance the interactions with tumor cells, and the cell capture efficacy is significantly improved. Since halloysite has no toxicity toward microorganisms, the bacteria composed within these nanotubes can be explored in oil/water emulsion for petroleum spilling bioremediation. Coating of living cells with halloysite can control the cell growth and is not harmful to their viability. Quantum dots immobilized on halloysite were employed for cell labeling and imaging. The concluding academic results combined with the abundant availability of these natural nanotubes promise halloysite applications in personal healthcare and environmental remediation.

UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma.

To explain the excess cancer rate in males, several candidates for "escape from X-inactivation tumor-suppressor" (EXITS) were recently identified. In this report we provide direct experimental evidence supporting UTX's role as an EXITS gene. Using a mouse lymphoma model, we show clear dosage effect of UTX copy number during tumorigenesis, which strongly supports the EXITS theory. Importantly, UTX deletion not only accelerates lymphomagenesis, it also strongly promotes tumor progression. UTX-knockout tumors are more aggressive, showing enhanced brain dissemination and formation of blood vessels. Efnb1 is overexpressed in UTX KO tumors and can lead to such phenotypes. In human patients, lymphomas with low UTX expression also express high levels of Efnb1, and cause significantly poor survival. Lastly, we show that UTX deficiency renders lymphoma sensitive to cytarabine treatment. Taken together, these data highlight UTX loss's profound impacts on tumor initiation and drug response.

Functionalization of Halloysite Nanotubes via Grafting of Dendrimer for Efficient Intracellular Delivery of siRNA.

Here, polyamidoamine grafted halloysite nanotubes (PAMAM- g-HNTs) were synthesized for loading of siRNA in order to intracellular delivery of siRNA and treat of breast cancer via gene therapy. The successful grafting of PAMAM on HNTs was confirmed by various analytical methods. The size, zeta potential, and grafting ratio of PAMAM- g-HNTs is ∼206.2 nm, +19.8 mV, and 3.04%, respectively. PAMAM- g-HNTs showed good cytocompatibility toward HUVECs (84.7%) and MCF-7 cells (82.3%) even at high concentration of 100 µg/mL. PAMAM- g-HNTs/siRNA exhibited enhanced cellular uptake efficiency of 94.3% compared with Lipofectamine 2000 (Lipo2000)/siRNA (83.6%). PAMAM- g-HNTs/small interfering RNA-vascular endothelial growth factor (siVEGF) led to 78.0% knockdown of cellular VEGF mRNA and induced 33.6% apoptosis in the MCF-7 cells, which is also much higher than that of Lipo2000/siVEGF. In vivo anti-cancer results demonstrated that PAMAM- g-HNTs/siVEGF treated 4T1-bearing mice showed enhanced anti-cancer efficacy than Lipo2000/siVEGF group. Also, the nanocarrier system showed negligible toxic effects toward the major organs of mice. In vivo fluorescence imaging studies showed that there is a slight decrease in the fluorescence signal of PAMAM- g-HNTs/cy5-siVEGF after 72 h post-injection. Therefore, PAMAM- g-HNTs show promising application as novel nanovectors for siRNA delivery and gene therapy of cancer.