Role of extracellular vesicles in insulin resistance: Signaling pathways, bioactive substances, miRNAs, and therapeutic potential.

Extracellular vesicles are small lipid bilayer particles that resemble the structure of cells and range in size from 30 to 1000 nm. They transport a variety of physiologically active molecules, such as proteins, lipids, and miRNAs. Insulin resistance (IR) is a pathological disease in which insulin-responsive organs or components become less sensitive to insulin's physiological effects, resulting in decreased glucose metabolism in target organs such as the liver, muscle, and adipose tissue. Extracellular vesicles have received a lot of attention as essential intercellular communication mediators in the setting of IR. This review looks at extracellular vesicles' role in IR from three angles: signaling pathways, bioactive compounds, and miRNAs. Relevant publications are gathered to investigate the induction, inhibition, and bidirectional regulation of extracellular vesicles in IR, as well as their role in insulin-related illnesses. Furthermore, considering the critical function of extracellular vesicles in regulating IR, the study analyzes the practicality of employing extracellular vesicles for medication delivery and the promise of combination therapy for IR.

Long-Acting Strategies for Antibody Drugs: Structural Modification, Controlling Release, and Changing the Administration Route.

Because of their high specificity, high affinity, and targeting, antibody drugs have been widely used in the treatment of many diseases and have become the most favored new drugs for research in the world. However, some antibody drugs (such as small-molecule antibody fragments) have a short half-life and need to be administered frequently, and are often associated with injection-site reactions and local toxicities during use. Increasing attention has been paid to the development of antibody drugs that are long-acting and have fewer side effects. This paper reviews existing strategies to achieve long-acting antibody drugs, including modification of the drug structure, the application of drug delivery systems, and changing their administration route. Among these, microspheres have been studied extensively regarding their excellent tolerance at the injection site, controllable loading and release of drugs, and good material safety. Subcutaneous injection is favored by most patients because it can be quickly self-administered. Subcutaneous injection of microspheres is expected to become the focus of developing long-lasting antibody drug strategies in the near future.

Stamped production of single-crystal hexagonal boron nitride monolayers on various insulating substrates.

Controllable growth of two-dimensional (2D) single crystals on insulating substrates is the ultimate pursuit for realizing high-end applications in electronics and optoelectronics. However, for the most typical 2D insulator, hexagonal boron nitride (hBN), the production of a single-crystal monolayer on insulating substrates remains challenging. Here, we propose a methodology to realize the facile production of inch-sized single-crystal hBN monolayers on various insulating substrates by an atomic-scale stamp-like technique. The single-crystal Cu foils grown with hBN films can stick tightly (within 0.35 nm) to the insulating substrate at sub-melting temperature of Cu and extrude the hBN grown on the metallic surface onto the insulating substrate. Single-crystal hBN films can then be obtained by removing the Cu foil similar to the stamp process, regardless of the type or crystallinity of the insulating substrates. Our work will likely promote the manufacturing process of fully single-crystal 2D material-based devices and their applications.

Kiwi-derived extracellular vesicles for oral delivery of sorafenib.

Sorafenib is an oral treatment for hepatocellular carcinoma (HCC). However, poor water solubility, harsh gastrointestinal environment and off-target effects contribute to the low bioavailability of oral sorafenib. Plant-derived extracellular vesicles (PDEVs) are biological nanovesicles with various bioactive functions that offer significant advantages in the field of oral drug delivery: protection from degradation by gastrointestinal fluids; crossing the intestinal epithelial barrier; specific targeting; safety; and abundant yield. However, there are fewer studies applying PDEVs for anti-tumor drug delivery to extra-digestive tissues. In this study, kiwifruit-derived extracellular vesicles (KEVs) were isolated and purified from kiwifruit, and their natural hepatic accumulation properties were exploited for targeted delivery of sorafenib (KEVs-SFB). Evidence showed that encapsulation of KEVs reduced the leakage of sorafenib in the gastrointestinal environment and enhanced the ability to cross the intestinal epithelium; KEVs-SFB was able to achieve liver accumulation and was predominantly taken up by HepG2 cells; KEVs-SFB was effective in inhibiting 4T1 cell proliferation; in the orthotopic liver cancer model, oral administration of KEVs-SFB inhibited tumor growth and improved the side effects of SFB. This PDEVs-based oral drug delivery platform is important for improving oral bioavailability and reducing drug side effects.

The Role of Small Interfering RNAs in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC), a primary liver cancer with high mortality, is the most common malignant tumor in the world. Currently, the effect of routine treatment is poor, especially for this kind of cancer with strong heterogeneity and late detection. In the past decades, the researches of gene therapy for HCC based on small interfering RNA have blossomed everywhere. This is a promising therapeutic strategy, but the application of siRNA is limited by the discovery of effective molecular targets and the delivery system targeting HCC. As the deepening of research, scientists have developed many effective delivery systems and found more new therapeutic targets. CONCLUSIONS: This paper mainly reviews the research on HCC treatment based on siRNA in recent years, and summarizes and classifies the HCC treatment targets and siRNA delivery systems.

A nano-targeted co-delivery system based on gene regulation and molecular blocking strategy for synergistic enhancement of platinum chemotherapy sensitivity in ovarian cancer.

Ovarian cancer (OC) has a low five-year survival rate, mainly because of its drug resistance to chemotherapy. It is the key to reverse drug resistance to combine multiple sensitization pathways to play a synergistic role. A nano scaled targeted co-delivery system (P123-PEI-G12, PPG) modified by bifunctional peptide tLyP-1-NLS (G12) was fabricated by using Pluronic P123 conjugated with low molecular weight polyethyleneimine (PEI). This delivery system can co-delivery Olaparib (Ola) and p53 plasmids to synergistically enhance the sensitivity of OC to platinum-based chemotherapy. P53@P123-PEI-G2/Ola (Co-PPGs) can achieve efficient tumor accumulation and cellular internalization through G12-mediated targeting. Co-PPGs then break down in the tumor cells, releasing the drug. Co-PPGs significantly enhanced the sensitivity of cisplatin (DDP) in platinum-resistant ovarian cancer (PROC) and synergistically inhibited the proliferation of PROC in vitro and in vivo. The sensitizing and synergistic effects of Co-PPGs were related to the activation of p53, inhibition of poly-ADP-ribose polymerase (PARP) and p-glycoprotein (P-gp) expression. This work provides a promising strategy for the effective treatment of PROC.

Applications and challenges of ultra-small particle size nanoparticles in tumor therapy.

With the development of nanotechnology, nanomedicines are widely used in tumor therapy. However, biological barriers in the delivery of nanoparticles still limit their application in tumor therapy. As one of the most fundamental properties of nanoparticles, particle size plays a crucial role in the process of the nanoparticles delivery process. It is difficult for large size nanoparticles with fixed size to achieve satisfactory outcomes in every process. In order to overcome the poor penetration of larger size, nanoparticles with ultra-small particle size are proposed, which are more conducive to deep tumor penetration and uniform drug distribution. In this review, the latest progresses and advantages of ultra-small nanoparticles are systematically summarized, the perspectives and challenges of ultra-small nanoparticles strategy for cancer treatment are also discussed.

Nano-composite hydrogels of Cu-Apa micelles for anti-vasculogenic mimicry.

Vasculogenic mimicry (VM) describes the phenomenon whereby fluid-conducting vessels are formed by highly invasive tumour cells, which supply blood to tumours during their early growth stages. Single antiangiogenic agents have limited inhibitory effects on VM, therefore, a multi-pathway anti-VM strategy is required. In this study, Apatinib (Apa) was coordinated with Cu2+ to form a Cu-Apa copper complex. The latter was loaded into oligo-hyaluronic acid (HA) polymeric micelles (HA-Chol) and subsequently embedded in Astragalus polysaccharide-based in situ hydrogels (APsGels) to generate Cu-Apa/HA-Chol@APsGels. In this system, Cu-Apa exerts the combined effects of Cu2+ and Apa to inhibit VM; HA-Chol micelles achieve targeted drug delivery and enhance endocytosis efficiency; APsGels realise sustained release of the drugs to ensure an anti-VM effect. This system demonstrated improved VM inhibition with low cytotoxicity and high biocompatibility, wound healing, and transwell invasion in three-dimensional cell cultured VM. Moreover, this system significantly inhibited VM formation and melanoma growth in a mouse tumour transplantation model. This study provides an effective strategy for inhibiting VM.

A cancer cell membrane coated nanoparticles-based gene delivery system for enhancing cancer therapy.

Gene therapy is a superior therapeutic means in cancer therapy. However, the instability of nucleic acid and the lack of suitable delivery carrier greatly restricts its further development and application. Herein, we coupled low molecular weight polyethyleneimine (LMW PEI) through disulfide bonds, then modified it with manganese dioxide (MnO2) nanosheets and nuclear localization signal peptide (NLS), as a p53 gene carrier, and finally coated it with B16F10 cell membrane to construct a novel gene-carrier system CM@MnO2-PEI-NLS-ss/p53 (M@MPNs/p53). Tumor cell membrane coating endows nanoparticles with homotypic targeting and immune escape capabilities, disulfide-crosslinked LMW-PEI has high transfection efficiency and low toxicity, and NLS peptides enhance nuclear delivery and improve p53 gene delivery efficiency; meanwhile, MnO2 nanosheets oxidize high intracellular concentration of glutathione (GSH), sensitizing p53 gene-mediated antitumor therapy. The results showed that the novel biofilm-camouflaged M@MPNs/p53 nanoparticles had a highly specific targeting effect on homologous cancer cells and could effectively inhibit tumor growth in vitro and in vivo. Besides, MnO2 loading improved p53-mediated tumor regression. This novel gene delivery platform is of great significance in improving gene delivery efficiency and enhancing anti-tumor therapy.

Continuous epitaxy of single-crystal graphite films by isothermal carbon diffusion through nickel.

Multilayer van der Waals (vdW) film materials have attracted extensive interest from the perspective of both fundamental research1-3 and technology4-7. However, the synthesis of large, thick, single-crystal vdW materials remains a great challenge because the lack of out-of-plane chemical bonds weakens the epitaxial relationship between neighbouring layers8-31. Here we report the continuous epitaxial growth of single-crystal graphite films with thickness up to 100,000 layers on high-index, single-crystal nickel (Ni) foils. Our epitaxial graphite films demonstrate high single crystallinity, including an ultra-flat surface, centimetre-size single-crystal domains and a perfect AB-stacking structure. The exfoliated graphene shows excellent physical properties, such as a high thermal conductivity of ~2,880 W m-1 K-1, intrinsic Young's modulus of ~1.0 TPa and low doping density of ~2.2 × 1010 cm-2. The growth of each single-crystal graphene layer is realized by step edge-guided epitaxy on a high-index Ni surface, and continuous growth is enabled by the isothermal dissolution-diffusion-precipitation of carbon atoms driven by a chemical potential gradient between the two Ni surfaces. The isothermal growth enables the layers to grow at optimal conditions, without stacking disorders or stress gradients in the final graphite. Our findings provide a facile and scalable avenue for the synthesis of high-quality, thick vdW films for various applications.

Advanced research on extracellular vesicles based oral drug delivery systems.

The oral route is the most convenient and simplest mode of administration. Nevertheless, orally administration of some commonly used therapeutic drugs, such as polypeptides, therapeutic proteins, small-molecule drugs, and nucleic acids, remains a major challenge due to the harsh gastrointestinal environment and the limited oral bioavailability. Extracellular vesicles (EVs) are diverse, nanoscale phospholipid vesicles that are actively released by cells and play crucial roles in intercellular communications. Some EVs have been shown to survive with the gastrointestinal tract (GIT) and can cross biological barriers. The potential of EVs to cross the GIT barrier makes them promising natural delivery carriers for orally administered drugs. Here, we introduce the uniqueness of EVs and their feasibility as oral drug delivery vehicles (ODDVs). Then we provide a general description of the different cellular EVs based oral drug delivery systems (ODDSs) currently under study and emphasize the contribution of endogenous features and multifunctional properties of EVs to the delivery performance. The current obstacles of moving EVs based ODDSs from bench to bedside are also discussed.

Research progress in the preparation, structural characterization, bioactivities, and potential applications of sulfated agarans from the genus Gracilaria.

The genus Gracilaria produces 80% of the world's industrial agar. Agar of this genus is a promising biologically active polymer, which has been used in the human diet and folk medicine, alternative for weight loss, treatment of diarrhea, etc. With more attention paid to the genus Gracilaria-sulfated agarans (GSAs), they exhibited multitudinous health benefits in antioxidant, antiviral, antibacterial, prebiotics, anti-tumor, anticoagulant, and antidiabetic. Various preparation procedures of GSAs making the diversities of structure and biological activity. Therefore, this review summarized the isolation, identification, bioactivity potentials, and applications of GSAs, providing a reference to the development of GSAs in functional food and pharmaceutical industry. PRACTICAL APPLICATIONS: The genus Gracilaria is known as a raw material for agar extraction. GSAs are food-grade agaran with the properties of thermoreversible gels at low concentrations, which are commonly used as an additive for making candies as well as raw material for making soup and snacks. They are used in folk medicine to treat diarrhea and other diseases. As an important bioactive macromolecule, GSAs have various biological activities (such as antioxidant, antiviral, antibacterial, probiotic, anti-tumor, anticoagulant, and antidiabetic activities), and have the potential to be developed as functional food and medicine. They could also be used to create innovative agar-based products such as antibacterial films and drug carriers.

Plant-derived extracellular vesicles as oral drug delivery carriers.

Oral administration is one of the most convenient and widely utilized methods of drug administration. However, many drugs were difficult to be administered orally due to their poor oral bioavailability. Designing a safe and effective oral drug delivery system is one of the basic strategies to overcome the poor oral bioavailability. Plant-derived extracellular vesicles (PDEVs) were found in a variety of plants and have similar physical and chemical properties to mammalian EVs. It has been proved that PDEVs can effectively encapsulate hydrophilic and hydrophobic drugs, remain stable in harsh gastrointestinal environments, and cross biological barriers to reach target tissues. Furthermore, the biological activity of PDEVs enables it to play a synergistic therapeutic role with drugs. In addition, the safety and high yield of PDEVs indicate their potential as oral drug carriers. In this review, we introduce the biogenesis, isolation, characterization and drug delivery methods of PDEVs, describe their stability, transport, delivery and therapeutic applications. Finally, the potential and challenges of PDEVs as drug carriers are discussed.

Mitochondrial targeted hierarchical drug delivery system based on HA-modified liposomes for cancer therapy.

Chemotherapy targeting mitochondrial is a faster and more sensitive anti-tumor therapy strategy. In this study, a hierarchical drug delivery system HA-GDT-Lip was constructed by coupling glycyrrhetinic acid (GA), triphenylphosphine (TPP), and doxorubicin (DOX), encapsulating them in cationic liposomes (CLs), then coating the surface of CLs with HA. HA-GDT-Lip nanoparticles can be accumulated in tumor tissue through the EPR effect, then achieve tumor cell-specific endocytosis mediated by the CD44 receptor, DOX can be successfully delivered into mitochondria through the combined action of GA and TPP. Physicochemical properties analysis showed that HA-GDT-Lip nanoparticles were uniform in size and spherical in shape. In vitro cell experiments showed that HA-GDT-Lip had high cell uptake efficiency and mitochondrial targeting ability. In addition, HA-GDT-Lip could induce MPTP opening and accelerate cell apoptosis. Meanwhile, HA-GDT-Lip showed excellent antitumor activity and in vivo safety in tumor-bearing nude mice. In conclusion, HA-GDT-Lip may serve as a promising mitochondrial delivery system to reduce the side effects of anticancer drugs and improve their antitumor efficacy.

Phragmites rhizoma polysaccharide-based nanocarriers for synergistic treatment of ulcerative colitis.

The purpose of this study was to construct Phragmites rhizoma polysaccharide-based nano-drug delivery systems (PRP2-SeNPs-H/Aza-Lips) for synergistically alleviating ulcerative colitis and to investigate the important roles of Phragmites rhizoma polysaccharide-based nanocarriers in PRP2-SeNPs-H/Aza-Lips. Phragmites rhizoma polysaccharide (PRP2) was isolated and used for the preparation of Phragmites rhizoma polysaccharide selenium nanoparticles with low selenium content (PRP2-SeNPs-L) and high selenium content (PRP2-SeNPs-H). Based on the electrostatic attraction between PRP2-SeNPs-H and azathioprine liposomes (Aza-Lips), PRP2-SeNPs-H/Aza-Lips were constructed for precise delivery of the model drug azathioprine (Aza) to colon lesions. Results showed that PRP2 significantly alleviated the clinical symptoms and colon tissue damage and down-regulated the levels of inflammatory factors in serum and colon, demonstrating beneficial effects on mice with ulcerative colitis. PRP2-SeNPs-L had better relieving effects on ulcerative colitis. Phragmites rhizoma polysaccharide-based nanocarriers may protect azathioprine liposomes against gastrointestinal digestion, enhance the therapeutic effects on ulcerative colitis, and significantly reduce liver damage from azathioprine, which helps to improve the efficacy and toxicity of clinical drugs.

Isolation, Structural Analysis and Anti-Inflammatory Activity of a Polysaccharide from Ilex cornuta Fruits.

In the present study, a polysaccharide from Ilex cornuta fruits (LCFP-3) was obtained by hot water extraction, Diethyaminoethyl cellulose-52 (DEAE-52) chromatography column and Sephadex G-100 gel column purification. Its structural characteristics were further explored using high performance anion exchange chromatography (HPAEC), gas chromatography and mass spectrometry (GC/MS), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy. Monosaccharide composition analysis revealed LCFP-3 contained mainly Galactose (31.92 %), Arabinose (25.87 %) and Galacturonic acid (23.35 %) while small percentage of Rhamnose, Glucose, Mannose and Xylose. Chemical composition analysis showed that the total sugar content of LCFP-3 was 90.31 % and the protein content was 0.246 %. Gel permeation chromatography (GPC) analysis showed that its average molecular weight was 41.199 kDa. Structural analysis showed that LCFP-3 may be composed of residues, T-α-Arap, T-α-Rhap, 1,3-α-Arap, 1,4-α-Arap, T-ß-Galp, 1,4-α-GalpA(OMe), 1,4-ß-Glcp, 1,3-ß-Galp, 1,3,6-ß-Manp, 1,6-ß-Galp, 1,3,4-ß-GalpA, 1,4,6-ß-Manp, 1,3,6-ß-Glcp, 1,2,3,4-α-Xylp. The anti-inflammatory activity of LCFP-3 was evaluated using lipopolysaccharide (LPS)-induced RAW246.7 macrophages. The results showed that 1-200 µg/mL LCFP-3 could dose-dependently protect against LPS-induced toxicity and 1 µg/mL LCFP-3 could significantly inhibit LPS-induced NO production. Therefore, LCFP-3 exerted an anti-inflammatory activity and has great potential as a functional ingredient.

Multifunctional metal complex-based gene delivery for tumour immune checkpoint blockade combination therapy.

Immune checkpoint blocking based on the PD-1/PD-L1 pathway has shown exciting results in various types of cancer. However, due to the off-target effect of PD-1/PD-L1 blocker, low tumour immunogenicity and tumour immunosuppressive microenvironment, a significant proportion of patients do not benefit from this treatment. Here, we constructed a novel multifunctional metal complex Fe/PEI-Tn by the coordination of polyethyleneimine (PEI) with Fe3+ and the modification of bifunctional peptides Tn containing the cell penetrating peptide (TAT) and nuclear localisation signal peptide (NLS), which was coated with hyaluronic acid (HA) to prolong the circulation time in vivo. Fe/PEI-Tn can condensate PD-L1 trap plasmid (pPD-L1 trap) and mediate PD-L1 trap protein expression in tumour tissues in situ, thus blocking the PD-1/PD-L1 pathway. Besides, Fe/PEI-Tn metal complex itself can act as an immune adjuvant to activate macrophages, reverse the phenotype of pro-tumour M2-type macrophages, and promote anti-tumour immunity. Meanwhile, Fe/PEI-Tn treatment can induce damage in tumour cells and release tumour-specific antigens into tumour microenvironment, thus stimulating anti-tumour immune response. Studies showed that HA/Fe/PEI-Tn/pPD-L1 trap complexes could promote the immune activation of tumour tissues and effectively delay tumour growth. This strategy provides a new direction for tumour combination therapy based on PD-1/PD-L1 blockade.

Robust growth of two-dimensional metal dichalcogenides and their alloys by active chalcogen monomer supply.

The precise precursor supply is a precondition for controllable growth of two-dimensional (2D) transition metal dichalcogenides (TMDs). Although great efforts have been devoted to modulating the transition metal supply, few effective methods of chalcogen feeding control were developed. Here we report a strategy of using active chalcogen monomer supply to grow high-quality TMDs in a robust and controllable manner, e.g., MoS2 monolayers perform representative photoluminescent circular helicity of ~92% and electronic mobility of ~42 cm2V-1s-1. Meanwhile, a uniform quaternary TMD alloy with three different anions, i.e., MoS2(1-x-y)Se2xTe2y, was accomplished. Our mechanism study revealed that the active chalcogen monomers can bind and diffuse freely on a TMD surface, which enables the effective nucleation, reaction, vacancy healing and alloy formation during the growth. Our work offers a degree of freedom for the controllable synthesis of 2D compounds and their alloys, benefiting the development of high-end devices with desired 2D materials.

Therapeutic strategies to overcome cisplatin resistance in ovarian cancer.

Ovarian cancer (OC) is one of the most common gynecologic tumors worldwide and one with the highest mortality. Cisplatin (DDP) is the first platinum-based complex approved by the Food and Drug Administration (FDA) to treat patients with OC. Despite a good initial response rate, most patients receiving DDP treatment will ultimately develop resistance via various complicated mechanisms, leading to therapeutic failure and increased mortality. Multiple resistance pathways have been identified as potentially key areas of intervention. In this review, chemotherapeutic drugs and phytochemicals developed to overcome cisplatin-resistance ovarian cancer (CROC) were discussed. Targeted inhibition or specific drugs are effective against the DDP-resistance phenotype by inhibiting resistance or increasing cytotoxic efficacy. Phytochemicals as chemosensitizers offer novel treatment strategies for CROC patients by reducing chemoresistance and increasing drug efficacy. Due to the complexity of the DDP-resistance mechanism, the treatment of OC needs to improve specificity and effectiveness, and multi-path cooperative therapy is undoubtedly one of the best options. We discuss extensively the role of combination therapy in reversing DDP-resistance in OC and the significance of using a nanoparticle delivery system in this context. Suggestions for potential therapeutic strategies for CROC treatment will help discover more effective and specific regimens to overcome DDP-resistance.

Multi-Mode Ultrasonic Guided Waves Based Damage Detection in L-Bars with Asymmetric Cross-Section with Sum of Multiple Signals Method.

Bars are significant load-carrying components in engineering structures. In particular, L-bars are typical structural components commonly used in truss structures and have typical irregular asymmetric cross-sections. To ensure the safety of load-carrying bars, much research has been done for non-destructive testing (NDT). Ultrasonic guided waves have been widely applied in various NDT techniques for bars as a result of the long-range propagation, low attenuation, and high sensitivity to damages. Though good for inspection of ultrasonic guided waves in symmetric cross-section bar-like structures, the application in asymmetric ones lacks further research. Moreover, traditional damage detection in bars using ultrasonic guided waves usually depends on a single-mode at a lower frequency with lower sensitivity and accuracy. To make full use of all frequencies and modes, a multi-mode characteristic-based damage detection method is presented with the sum of multiple signals (SoM) strategy for L-bars with asymmetric cross-section. To control the desired mode in multi-mode ultrasonic guided waves, excitation optimization and weighted gathering are carried out by the analysis of the semi-analytical finite element (SAFE) method and the normal mode expansion (NME) method. An L-bar example with the asymmetric cross-section of 35 mm × 20 mm × 3 mm is used to specialize the proposed method, and some finite element (FE) models have been simulated to validate the mode control. In addition, one PZT is applied as a contrast in order to validate the multielement mode control. Then, more FE simulations experiments for damage detection have been performed to validate the damage detection method and verify the improvement in detection accuracy and damage sensitivity.