Nanozymes: a new approach for leukemia therapy.

Leukemia is a type of clonal disorder of hematopoietic stem and progenitor cells characterized by bone marrow failure, differentiation arrest, and lineage skewing. Despite leukemia being a complex disease and it being difficult to identify a single driving force, redox homeostasis, the balance between reactive oxygen species (ROS) producers and cellular antioxidant systems, is normally impaired during leukemogenesis. In this context, the modulation of ROS in leukemia cells can be harnessed for therapeutic purposes. Nanozymes are functional nanomaterials with enzyme-like characteristics, which address the intrinsic limitations of natural enzymes and exhibit great potential in synergistic antitumor therapy. Nanozymes possess catalytic activities (e.g., peroxidase-like activity, catalase-like activity, superoxide dismutase-like activity, and oxidase-like activity) to regulate ROS levels in vitro and in vivo, making them promising for leukemia therapy. On account of the rapid development of nanozymes recently, their application potentials in leukemia therapy are gradually being explored. To highlight the achievements of nanozymes in the leukemia field, this review summarizes the recent studies of nanozymes with anti-leukemia efficacy and the underlying mechanism. In addition, the challenges and prospects of nanozyme research in leukemia therapy are discussed.

Biomimetic Mineralized CRISPR/Cas RNA Nanoparticles for Efficient Tumor-Specific Multiplex Gene Editing.

CRISPR/Cas9 systems have great potential to achieve sophisticated gene therapy and cell engineering by editing multiple genomic loci. However, to achieve efficient multiplex gene editing, the delivery system needs adequate capacity to transfect all CRISPR/Cas9 RNA species at the required stoichiometry into the cytosol of each individual cell. Herein, inspired by biomineralization in nature, we develop an all-in-one biomimetic mineralized CRISPR/Cas9 RNA delivery system. This system allows for precise control over the coencapsulation ratio between Cas9 mRNA and multiple sgRNAs, while also exhibiting a high RNA loading capacity. In addition, it enhances the storage stability of RNA at 4 °C for up to one month, and the surface of the nanoparticles can be easily functionalized for precise targeting of RNA nanoparticles in vivo at nonliver sites. Based on the above characteristics, as a proof-of-concept, our system was able to achieve significant gene-editing at each target gene (Survivin: 31.9%, PLK1: 24.41%, HPV: 23.2%) and promote apoptosis of HeLa cells in the mouse model, inhibiting tumor growth without obvious off-target effects in liver tissue. This system addresses various challenges associated with multicomponent RNA delivery in vivo, providing an innovative strategy for the RNA-based CRISPR/Cas9 gene editing.

Neural network-based optimization of sub-diffuse reflectance spectroscopy for improved parameter prediction and efficient data collection.

In this study, a general and systematical investigation of sub-diffuse reflectance spectroscopy is implemented. A Gegenbauer-kernel phase function-based Monte Carlo is adopted to describe photon transport more efficiently. To improve the computational efficiency and accuracy, two neural network algorithms, namely, back propagation neural network and radial basis function neural network are utilized to predict the absorption coefficient µ a , reduced scattering coefficient µ s ' and sub-diffusive quantifier γ , simultaneously, at multiple source-detector separations (SDS). The predicted results show that the three parameters can be predicated accurately by selecting five SDSs or above. Based on the simulation results, a four wavelength (520, 650, 785 and 830 nm) measurement system using five SDSs is designed by adopting phase-lock-in technique. Furtherly, the trained neural-network models are utilized to extract optical properties from the phantom and in vivo experimental data. The results verify the feasibility and effectiveness of our proposed system and methods in mucosal disease diagnosis.

Bionic Regulators Break the Ecological Niche of Pathogenic Bacteria for Modulating Dysregulated Microbiome in Colitis.

Therapeutic approaches that reprogram the gut microbiome are promising strategies to alleviate and cure inflammatory bowel disease (IBD). However, abnormal expansion of Escherichia coli during inflammation can promote pathogenic bacteria occupying ecological niches to resist reprogramming of the microbiome. Herein, a bionic regulator (CaWO4 @YCW) is developed to efficiently and precisely regulate the gut microbiome by specifically suppressing the abnormal expansion of E. coli during colitis and boosting probiotic growth. Inspired by the binding of E. coli strains to the mannose-rich yeast cell wall (YCW), YCW is chosen as the bionic shell to encapsulate CaWO4 . It is demonstrated that the YCW shell endows CaWO4 with superior resistance to the harsh environment of the gastrointestinal tract and adheres to the abnormally expanded E. coli in colitis, specifically as a positioner. Notably, the high expression of calprotectin at the colitis site triggers the release of tungsten ions through calcium deprivation in CaWO4 , thus inhibiting E. coli growth by replacing molybdenum in the molybdopterin cofactor. Moreover, YCW functions as a prebiotic and promotes probiotic growth. Consequently, CaWO4 @YCW can efficiently and precisely reprogram the gut microbiome by eliminating pathogenic bacteria and providing prebiotics, resulting in an extraordinary therapeutic advantage for DSS-induced colitis.

Potential nanotherapeutic strategies for perioperative stroke.

AIMS: Based on the complex pathological environment of perioperative stroke, the development of targeted therapeutic strategies is important to control the development of perioperative stroke. DISCUSSIONS: Recently, great progress has been made in nanotechnology, and nanodrug delivery systems have been developed for the treatment of ischemic stroke. CONCLUSION: In this review, the pathological processes and mechanisms of ischemic stroke during perioperative stroke onset were systematically sorted. As a potential treatment strategy for perioperative stroke, the review also summarizes the multifunctional nanodelivery systems based on ischemic stroke, thus providing insight into the nanotherapeutic strategies for perioperative stroke.

In Vivo Activation of T-Cell Proliferation by Regulating Cell Surface Receptor Clustering Using a pH-Driven Interlocked DNA Nano-Spring.

Activation of T-cell proliferation specifically in a tumor is crucial for reducing the autoimmune side effects of antitumor immunotherapy. Herein, we developed a pH-driven interlocked DNA nano-spring (iDNS) to stimulate T-cell activation in vivo in response to the low pH value in a tumor microenvironment. The interlocked structure of iDNS provide a more rigid scaffold in comparison to double-stranded DNA for ligand assembly, which can help to control the spatial distribution of ligands with more accuracy. We have demonstrated that the pH-driven reversible reconfiguration of iDNS provides a powerful way to regulate the nanoscale distribution of T-cell receptors (CD3) on the cell surface. The relatively low pH value (pH 6.5) in a solid tumor was able to drive the springlike shrinking of iDNS and induce significant T-cell proliferation, leading to an enhanced antitumor effect, thus providing a tool for specifically inducing an immune response in a tumor for immunotherapy.

Nano-enabled Tumor Systematic Energy Exhaustion via Zinc (II) Interference Mediated Glycolysis Inhibition and Specific GLUT1 Depletion.

Despite the promise of tumor starvation therapies, they are often associated with nonspecific and incomplete energy blockade. Here, a novel paradigm of starvation therapy is proposed to synergize the "Zn2+ interference"-mediated glycolysis inhibition and Zn2+ -activating GLUT1 (Glucose transporter 1) tumor specific depletion for systematic energy exhaustion. It is discovered that ZIF-8 (zinc imidazolate metal-organic frameworks ) can induce abrupt intracellular Zn2+ elevation preferentially in melanoma cells, and then achieve effective glycolysis blockade through "Zn2+ interference"-triggered decrease of NAD+ and inactivation of GAPDH, making it a powerful tumor energy nanoinhibitor. Meanwhile, Zn2+ -activating DNAzymes for specifically cleaving GLUT1 mRNA is designed. This DNAzyme can only be activated under intracellular Zn2+ overloading, and then directionally cut off glucose supply, which further restrains the adaptive up-regulation of glycolytic flux after glycolysis inhibition in tumors. Afterward, DNAzymes are loaded in ZIF-8 concurrently tethered by hyaluronic acid (HA), constructing a "nanoenabled energy interrupter ". Such a rational design presents a preferential accumulation tendency to tumor sites due to the active CD44-targeting mechanisms, specifically achieves remarkable systematic energy exhaustion in melanoma cells, and affords 80.8% in tumor growth suppression without systemic toxicity in vivo. This work verifies a fascinating therapeutic platform enabling ion interference-inductive starvation strategy for effective tumor therapy.

Limiting tumor cells comprehensively at micro and macro levels to improve the therapeutic effect of chemotherapy.

Clinical data shows that antitumor treatments are often ineffective if tumor cells have metastasized. To gain an effective antitumor therapeutic effect, in this report, the tumor cell was limited to the primary site and simultaneously ablated by chemotherapy. Considering the extremely complicated process of cancer metastasis, we seek to comprehensively suppress tumor metastases at both micro and macro levels, which closely link to migration and interact with each other. At the micro level, the motility of the tumor cell was decreased via accelerating mitochondria fusion. At the macro level, the unfavorable hypoxia environment was improved. A liposome-based multifunctional nanomedicine was designed by coloading latrunculin B (LAT-B), an inhibitor of actin polymerization, and doxorubicin (DOX) into the hydrophobic bilayers and aqueous cavity, respectively. Meanwhile, an oxygen reservoir named perfluoropentane (PFP) was encapsulated into the liposome core to fulfill synergistic treatment of metastatic tumors. In this paper, we demonstrated that the metastasis of the tumor cell could be effectively inhibited by LAT-B through promoting mitochondria fusion without affecting its function, making it as an encouraging candidate for effective anti-metastasis therapy. Meanwhile, we found that the combination of LAT-B and DOX shows a synergistic effect against tumors because the combined effect of these two drugs cover the entire cell proliferation process. In a word, this report presents a potential improvement in the treatment of metastatic cancer.

A soft anti-virulence liposome realizing the explosive release of antibiotics at an infectious site to improve antimicrobial therapy.

Pore-forming toxins (PFTs), the most common virulence proteins, are promising therapeutic keys in bacterial infections. CAL02, consisting of sphingomyelin (Sm) and containing a maximum ratio of cholesterol (Ch), has been applied to sequester PFTs. However, Sm, a saturated phospholipid, leads to structural rigidity of the liposome, which does not benefit PFT combination. Therefore, in order to decrease the membrane rigidity and improve the fluidity of liposomes, we have introduced an unsaturated phospholipid, phosphatidylcholine (Pc), to the saturated Sm. In this report, a soft nanoliposome (called CSPL), composed of Ch, Sm and Pc, was artificially prepared. In order to further improve its antibacterial effect, vancomycin (Van) was loaded into the hydrophilic core of CSPL, where Van can be released radically at the infectious site through transmembrane pores formed by the PFTs in CSPL. This soft Van@CSPL nanoliposome with detoxification/drug release was able to inhibit the possibility of antibiotic resistance and could play a better role in treating severe invasive infections in mice.

Nanoenabled Disruption of Multiple Barriers in Antigen Cross-Presentation of Dendritic Cells via Calcium Interference for Enhanced Chemo-Immunotherapy.

Chemo-immunotherapy holds the advantage of specific antitumor effects by activating T cell immune response. However, the efficiency of chemo-immunotherapy is restricted to the insufficient antigen presentation of dendritic cells (DCs) in the tumor immunosuppression microenvironment. Here, we rationally designed a simple yet versatile calcium ion nanogenerator to disrupt the autophagy inhibition condition within DCs, enrich damage-associated molecular patterns (DAMPs), and attenuate acidity in the tumor microenvironment. After chemotherapy, honeycomb calcium carbonate (CaCO3) nanoparticles (OVA@CaCO3, denoted as HOCN, ovalbumin (OVA) acted as skeleton) could preferentially accumulate in the tumor and display a series of benefits for disrupting multiple barriers in antigen cross-presentation of DCs: (i) recovering cell viability of DCs by HOCN-induced tumor acidity attenuating; (ii) disrupting the autophagy inhibition condition in DCs by generating Ca2+ in cells; (iii) improving maturation of DCs by Ca2+ overloading-mediated enhanced DAMP release from tumor cells. In addition, HOCN can also disrupt the immunosuppressive microenvironment by reducing the infiltration of immunosuppressive cells and factors. We believe regulation of the intratumoral Ca2+ offers an alternative strategy for improving cancer chemo-immunotherapy.

Self-responsive co-delivery system for remodeling tumor intracellular microenvironment to promote PTEN-mediated anti-tumor therapy.

Delivering the pten gene into tumor cells to reacquire PTEN functionality is considered to be an attractive method for cancer treatment. However, the inhibition effect of the tumor intracellular microenvironment (TIME), especially at the high reactive oxygen species (ROS) level, on pten expression and PTEN protein functionality was nearly overlooked. Herein, the development of a potential strategy is described, which enhances PTEN-mediated anti-tumor capability by exhausting the intracellular ROS in TIME. To achieve this, poly(ethyleneimine) (PEI)-modified DSPE was introduced to protect the pten plasmid, and form liposomes for encapsulating the "scavenger" of oxidation homeostasis, epigallocatechin-3-gallate (EGCG). Notably, this was a simple system with improved safety compared which when compared with the use of PEI could accomplish efficient pten transfection and simultaneous disintegration to cause transient release of EGCG responding to the endosome environment through the "proton sponge effect". In the cytoplasm, EGCG depleted ROS and promoted the expression of the pten gene as well as restoring protein functionality, thus negatively regulating the PI3K-AKT signaling pathway. In vitro and in vivo results revealed that this system significantly inhibited tumor growth via remodeling of the TIME, and provided a promising way to control malignant tumors.

Sequential Intercellular Delivery Nanosystem for Enhancing ROS-Induced Antitumor Therapy.

Despite recent advances in enhancing photodynamic therapy efficacy, high-efficiency reactive oxygen species (ROS)-based therapy approach, especially in malignancy tumor treatment, remains challenging. Relieving the hypoxia of tumor tissue has been considered to be an attractive strategy for enhancing ROS-based treatment effect. Nevertheless, it is frequently neglected that the hypoxic regions are usually located deep in the tumors and therefore are usually inaccessible. To address these limitations, herein we constructed a sequential intercellular delivery system (MFLs/LAOOH@DOX) that consists of a membrane fusion liposomes (MFLs) doped with linoleic acid hydroperoxide (LAOOH) in the lipid bilayer and antitumor doxorubicin (DOX) encapsulated inside. In this report, LAOOH, one of the primary products of lipid peroxidation in vivo, was selected as ROS-generated agent herein, which depends on Fe2+ rather than oxygen and other external stimuli to produce ROS. Upon the enhanced permeation and retention effect, MFLs/LAOOH@DOX first fused with tumor cell membranes in the perivascular region in synchrony with selective delivery of LAOOH into the plasma membrane and the on-demand intracellular release of DOX. By hitchhiking with extracellular vesicles, LAOOH, as a cell membrane natural ingredient, spread gradually to neighboring cells and throughout the entire tumor eventually. Combined with subsequent administration of nano Fe3O4, ROS was specifically generated on the tumor cell membrane by LAOOH throughout the tumor tissues. This study offers a new method to enhance ROS-based antitumor treatment efficiency.

Personalized Cancer Immunotherapy via Transporting Endogenous Tumor Antigens to Lymph Nodes Mediated by Nano Fe3 O4.

While immunotherapy has a tremendous clinical potential to combat cancer, immune responses generated by conventional cancer immunotherapy remain not enough to completely eliminate tumors, mainly due to the tumor's immunosuppressive microenvironment and heterogeneity of tumor immunogenicity. To improve antitumor immune responses and realize personalized immunotherapy, in this report, endogenous tumor antigens (ETAs) that dynamically present on tumor cells are transported to lymph nodes (LNs). Based on the hypothesis that nano Fe3 O4 (≈10 nm) could serve as the nanocarrier for transporting ETAs from the tumor to LNs, we wondrously find that Fe3 O4 has a tremendous potential to improve cancer immunotherapy, because of its excellent protein-captured efficiency and LNs-targeted ability. To ensure the optimal ETAs-bound efficiency of Fe3 O4 , a core-shell formulation (denoted as Ce6/Fe3 O4 -L) is developed and specific release of Fe3 O4 in tumor is enabled. These findings provide a simple and general strategy for boosting cytotoxic T-cell response and realizing personalized cancer immunotherapy simultaneously.

Aggregation of sodium 1-(n-alkyl)naphthalene-4-sulfonates in aqueous solution: micellization and microenvironment characteristics.

In aqueous solution, the micellization and microenvironment characteristics of the micelle assemblies of three anionic surfactants, sodium 1-(n-alkyl)naphthalene-4-sulfonates (SANS), have been investigated by steady-state fluorescence and time-resolved fluorescence decay techniques using pyrene, Ru(bpy)3(2+), and 1,6-diphenyl-1,3,5-hexatriene as fluorescence probes. The critical micelle concentrations (cmc's), effective carbon atom numbers (neff's), hydrophilic-lipophilic balances (HLBs), mean micelle aggregation numbers, micropolarities, and microviscosities of these surfactant micelles have been determined. The logarithmic cmc of the alkylnaphthalene sulfonates decreases linearly with an increase in the neff. The logarithmic aggregation number of the alkylnaphthalene sulfonates increases linearly with an increase in the neff. However, in contrast to the alkylsufonates and the alkylbenzene sulfonates, the aggregation for these alkylnaphthalene sulfonate molecules is less sensitive to the increase in the neff. The micropolarity of these alkylnaphthalene sulfonate micelles is less sensitive to the increase in the alkyl chain length and is lower than that of sodium dodecyl sulfate (SDS). The microviscosity of these alkylnaphthalene sulfonate micelles increases with an increase in the alkyl chain length and is lower than those of nonionic surfactants and zwitterionic surfactants. These results suggest that naphthyl rings have a notable effect on the micellization of SANS.

Studies of synergism for lowering dynamic interfacial tension in sodium alpha-(n-alkyl) naphthalene sulfonate/alkali/acidic oil systems.

Alkylnaphthalene sulfonates with high purity were selected as model components to research synergism for lowering interfacial tension (IFT) in surfactant/alkali/acidic oil systems. The dynamic IFTs between alkylnaphthalene sulfonates with different alkyl chain length and n-decane, oleic acid model oil, or Shengli crude oil were measured. The results showed that the alkylnaphthalene sulfonates with different alkyl chain lengths had different synergism with different acidic components and their ionized acids under the same conditions. The synergism for lowering dynamic IFT in alkylnaphthalene sulfonate/alkali/acidic oil systems was controlled by alkylnaphthalene sulfonate concentration, alkyl chain length, alkali concentration, alkali type, and oleic acid concentration: optimal physicochemical conditions were necessary to the best synergism. This indicates that the synergism among added surfactant acidic components in crude oil and their ionized acids is controlled by the ratio of their interfacial concentrations.

A Study of Thin Liquid Films as Related to the Stability of Crude Oil Emulsions.

In this paper, we report the influence of surface-active compounds on the stability of crude oil emulsions using the apparatus designed for bilayer lipid membrane studies. The results obtained show that natural surface-active materials in crude oil, such as petroleum acids and asphaltenes, play a pivotal role. The ionized acids formed by the reaction between the petroleum acids and the alkali can decrease the interfacial tension and accelerate the thinning as well as the breakdown of the thin liquid film. The asphaltenes can adsorb onto the interface and improve the stability of the film. The order of the stability of the films between crude oil and alkaline solutions is found to be as follows: crude oil with asphaltenes removed (ii)

Applications of High-Temperature Aqueous Media for Synthetic Organic Reactions.

Preparative organic synthesis was investigated in aqueous media at temperatures up to 300 degrees C. Experiments were conducted with a recently disclosed pressurized microwave batch reactor (MBR) or in conventionally heated autoclaves. Thirty-six examples are presented. Among these, methods were developed for a Fischer synthesis, an intramolecular aldol condensation that was scaled up, decarboxylation of indole-2-carboxylic acid, Rupe rearrangement of 1-ethynyl-1-cyclohexanol, isomerization of carvone to carvacrol, and conversion of phenylacetylene to acetophenone. The applicability of high-temperature water was also demonstrated for biomimetic processes important in food, flavor, and aroma chemistry and for tandem reactions such as formation of 2-methyl-2,3-dihydrobenzofuran from allyl phenyl ether. When addition of acid or base was necessary, less agent was usually required for high-temperature processes than for those at and below boiling, and the reactions often proceeded more selectively. In some instances the requirement was orders of magnitude lower, with obvious consequences for safe, economic processing and for lowering costs of effluent disposal. The diversity of reactions indicates that high-temperature aqueous media could play an increasingly important role in the development of new preparative processes.