Epigenetics regulation during virus-host interaction and their effects on the virus and host cell.

Epigenetics, a field of study focused on cellular gene regulation independent of DNA sequence alterations, encompasses DNA methylation, histone modification and microRNA modification. Epigenetics processes play a pivotal role in governing the life cycles of viruses, enabling their transmission, persistence, and maintenance with in host organisms. This review examines the epigenetics regulation of diverse virus including orthomoxyviruses, coronavirus, retroviridae, mononegavirales, and poxviruses among others. The investigation encompasses ten representative viruses from these families. Detailed exploration of the epigenetic mechanisms underlying each virus type, involving miRNA modification, histone modification and DNA methylation, sheds light on the intricate and multifaceted epigenetic interplay between viruses and their hosts. Furthermore, this review investigates the influence of these epigenetic processes on infection cycles, emphasizing the utilization of epigenetics by viruses such as Epstein-Barr virus and Human immunodeficiency virus (HIV) to regulate gene expression during chronic or latent infections, control latency, and transition to lytic infection. Finally, the paper explores the novel treatments possibilities stemming from this epigenetic understanding.

Arsenic Prodrug-Mediated Tumor Microenvironment Modulation Platform for Synergetic Glioblastoma Therapy.

Glioblastoma (GBM) has a distinct internal environment characterized by high levels of glutathione (GSH) and low oxygen partial pressure, which significantly restrict most drugs' effectiveness. Arsenic-based drugs are emerging candidates for treating solid tumors; however, relatively high doses in solo systems and inconsistent complementary systems severely damage the normal tissues. We proposed a novel covalently conjugated strategy for arsenic-based therapy via arsenic-boronic acid complex formation. The boronic acid was modified on silver (AgL) to capture AsV under an alkaline condition named arsenate plasmonic complex (APC) with a distinct Raman response. The APC can precisely release the captured AsV in lysosomal acidic pH that specifically targets TME to initiate a multimodal therapeutic effect such as GSH depletion and reactive oxygen species generation. In addition, GSH activation leads to subconverted AsV into AsIII, which further facilitated glutathione peroxidase (GPx) and superoxide dismutase inhibition, whereas the tumor selective etching of the silver core triggered by endogenous H2O2 that can oxidize to generate highly toxic Ag ions produces and supplies O2 to help the alleviated hypoxia. Both in vitro and in vivo data verify the APC-based chemotherapy paving the way for efficient nanomedicine-enabled boronate affinity-based arsenic chemotherapeutics for on demand site-specific cancer combination treatment of GBM tumors.

Targeted liposomes for combined delivery of artesunate and temozolomide to resistant glioblastoma.

The effective treatment of glioblastoma (GBM) is a great challenge because of the blood-brain barrier (BBB) and the growing resistance to single-agent therapeutics. Targeted combined co-delivery of drugs could circumvent these challenges; however, the absence of more effective combination drug delivery strategies presents a potent barrier. Here, a unique combination ApoE-functionalized liposomal nanoplatform based on artesunate-phosphatidylcholine (ARTPC) encapsulated with temozolomide (ApoE-ARTPC@TMZ) was presented that can successfully co-deliver dual therapeutic agents to TMZ-resistant U251-TR GBM in vivo. Examination in vitro showed ART-mediated inhibition of DNA repair through the Wnt/ß-catenin signaling cascade, which also improved GBM sensitivity to TMZ, resulting in enhanced synergistic DNA damage and induction of apoptosis. In assessing BBB permeation, the targeted liposomes were able to effectively traverse the BBB through low-density lipoprotein family receptors (LDLRs)-mediated transcytosis and achieved deep intracranial tumor penetration. More importantly, the targeted combination liposomes resulted in a significant decrease of U251-TR glioma burden in vivo that, in concert, substantially improved the survival of mice. Additionally, by lowering the effective dosage of TMZ, the combination liposomes reduced systemic TMZ-induced toxicity, highlighting the preclinical potential of this novel integrative strategy to deliver combination therapies to brain tumors.

Heme Oxygenase-1 targeting exosomes for temozolomide resistant glioblastoma synergistic therapy.

Glioblastoma (GBM) is a highly fatal and recurrent brain cancer without a complete prevailing remedy. Although the synthetic nanotechnology-based approaches exhibit excellent therapeutic potential, the associated cytotoxic effects and organ clearance failure rest major obstacles from bench to clinics. Here, we explored allogeneic bone marrow mesenchymal stem cells isolated exosomes (BMSCExo) decorated with heme oxygenase-1 (HMOX1) specific short peptide (HSSP) as temozolomide (TMZ) and small interfering RNA (siRNA) nanocarrier for TMZ resistant glioblastoma therapy. The BMSCExo had excellent TMZ and siRNA loading ability and could traverse the blood-brain barrier (BBB) by leveraging its intrinsic brain accumulation property. Notably, with HSSP decoration, the TMZ or siRNA encapsulated BMSCExo exhibited excellent TMZ resistant GBM targeting ability both in vitro and in vivo due to the overexpression of HMOX1 in TMZ resistant GBM cells. Further, the HSSP decorated BMSCExo delivered the STAT3 targeted siRNA to the TMZ resistant glioma and restore the TMZ sensitivity, consequently achieved the synergistically drug resistant GBM treatment with TMZ. Our results showed this biomimetic nanoplatform can serve as a flexible, robust and inert system for GBM treatment, especially emphasizing the drug resistant challenge.

Correction: SERS-based nanostrategy for rapid anemia diagnosis.

Correction for 'SERS-based nanostrategy for rapid anemia diagnosis' by Pir Muhammad et al., Nanoscale, 2020, 12, 1948-1957, DOI: 10.1039/C9NR09152A.

Stimuli-responsive prodrug-based cancer nanomedicine.

The rapid development of nanotechnology results in the emergence of nanomedicines, but the effective delivery of drugs to tumor sites remains a great challenge. Prodrug-based cancer nanomedicines thus emerged due to their unique advantages, including high drug load efficiency, reduced side effects, efficient targeting, and real-time controllability. A distinctive characteristic of prodrug-based nanomedicines is that they need to be activated by a stimulus or multi-stimulus to produce an anti-tumor effect. A better understanding of various responsive approaches could allow researchers to perceive the mechanism of prodrug-based nanomedicines effectively and further optimize their design strategy. In this review, we highlight the stimuli-responsive pathway of prodrug-based nanomedicines and their anticancer applications. Furthermore, various types of prodrug-based nanomedicines, recent progress and prospects of stimuli-responsive prodrug-based nanomedicines and patient data in the clinical application are also summarized. Additionally, the current development and future challenges of prodrug-based nanomedicines are discussed. We expect that this review will be valuable for readers to gain a deeper understanding of the structure and development of prodrug-based cancer nanomedicines to design rational and effective drugs for clinical use.

Nanomedicine-based immunotherapy for central nervous system disorders.

Central nervous system (CNS) disorders represent a broad spectrum of brain ailments with short- and long-term disabilities, and nanomedicine-based approaches provide a new therapeutic approach to treating CNS disorders. A variety of potential drugs have been discovered to treat several neuronal disorders; however, their therapeutic success can be limited by the presence of the blood-brain barrier (BBB). Furthermore, unique immune functions within the CNS provide novel target mechanisms for the amelioration of CNS diseases. Recently, various therapeutic approaches have been applied to fight brain-related disorders, with moderate outcomes. Among the various therapeutic strategies, nanomedicine-based immunotherapeutic systems represent a new era that can deliver useful cargo with promising pharmacokinetics. These approaches exploit the molecular and cellular targeting of CNS disorders for enhanced safety, efficacy, and specificity. In this review, we focus on the efficacy of nanomedicines that utilize immunotherapy to combat CNS disorders. Furthermore, we detailed summarize nanomedicine-based pathways for CNS ailments that aim to deliver drugs across the BBB by mimicking innate immune actions. Overview of how nanomedicines can utilize multiple immunotherapy pathways to combat CNS disorders.

pH-Dependent Slipping and Exfoliation of Layered Covalent Organic Framework.

Layered/two-dimensional covalent organic frameworks (2D COF) are crystalline porous materials composed of light elements linked by strong covalent bonds. Interlayer force is one of the main factors directing the formation of a stacked layer structure, which plays a vital role in the stability, crystallinity, and porosity of layered COFs. The as-developed new way to modulate the interlayer force of imine-linked 2D TAPB-PDA-COF (TAPB = 1,3,5-tris(4-aminophenyl)benzene, PDA = terephthaldehyde) by only adjusting the pH of the solution. At alkaline and neutral pH, the pore size of the COF decreases from 34 Šdue to the turbostratic effect. Under highly acidic conditions (pH 1), TAPB-PDA-COF shows a faster and stronger turbostratic effect, thus causing the 2D structure to exfoliate. This yields bulk quantities of an exfoliated few/single-layer 2D COF, which was well dispersed and displayed a clear Tyndall effect (TE). Furthermore, nanopipette-based electrochemical testing also confirms the slipping of layers with increase towards acidic pH. A model of pH-dependent layer slipping of TAPB-PDA-COF was proposed. This controllable pH-dependent change in the layer structure may open a new door for potential applications in controlled gas adsorption/desorption and drug loading/releasing.

Mass Transfer Modulation and Gas Mapping Based on Covalent Organic Frameworks-Covered Theta Micropipette.

Covalent organic frameworks (COFs) consist nanochannels that are fundamentally important for their application. Up to now, the effect of gas phase on COF nanochannels are hard to explore. Here, TAPB-PDA-COFs (triphenylbenzene-terephthaldehyde-COFs) was synthesized in situ at the tip of a theta micropipette. The COF-covered theta micropipette (CTP) create a stable gas-liquid interface inside the COF nanochannels, through which the humidity-modulated ion mass transfer in the COF nanochannels can be recorded by recording the current across the two channels of the theta micropipette. Results show that the humid air changes the mobility of the ions inside the COF nanochannels, which leads to the change of ionic current. Humid air showed different effects on the ion transfer depending on the solvent polarity index and vapor pressure. Current decreases linearly with the increase of relative humidity (RH) from 11% to 98%. The CTP was also mounted on the scanning electrochemical microscopy as a probe electrode for mapping micrometer-scale humidity distribution.

SERS-based nanostrategy for rapid anemia diagnosis.

Iron detection is one of the critical markers to diagnose multiple blood-related disorders that correspond to various biological dysfunctions. The currently available anemia detection approach can be used only for pre-treated blood samples that interfere with the actual iron level in blood. Real-time detection approaches with higher sensitivity and specificity are certainly needed to cope with the commercial level clinical analyses. Herein, we presented a novel strategy to determine the blood iron that can be easily practiced at commercial levels. The blend of well-known iron-cyanide chemistry with nanotechnology is advantageous with ultrahigh sensitivity in whole blood analysis without any pre-treatments. This approach is a combined detection system of the conventional assay (UV-visible spectroscopy) with surface-enhanced Raman scattering (SERS). Organic cyanide modified silver nanoparticles (cAgNPs) can selectively respond to Fe3+ ions and Hb protein with a detection limit of 10 fM and 0.46 µg mL-1, respectively, without being affected by matrix interfering species in the complex biological fluid. We confirmed the clinical potential of our new cAgNPs by assessing iron-status in multiple anemia patients and normal controls. Our SERS-based iron quantitation approach is highly affordable for bulk-samples, cheap, quick, flexible, and useful for real-time clinical assays. Such a method for metal-chelation has extendable features of therapeutics molecular tracking within more complex living systems at cellular levels.

Size-Controllable Gold Nanopores with High SERS Activity.

Nanopore structures have been successfully employed in next-generation DNA sequencing. For more complicated protein which normally contains 20 different amino acids, identifying the fluctuation of ionic current caused by different amino acids appears inadequate for protein sequencing. Therefore, it is highly desirable to develop size-controllable nanopores with optical activity that can provide additional structural information. Herein, we discovered the novel nanopore properties of the self-assembled ultramicroelectrodes originally developed by Bard and co-workers. Using a slightly modified method, the self-assembly of 7 ± 1 nm gold nanoparticles (AuNPs) can be precisely controlled to form a gold nanoporous sphere (GPS) on the tip of a glass capillary. Different dithiol linker molecules (1,3-propanedithiol, C3; 1,6-hexanedithiol, C6; and 1,9-nonanedithiol, C9) reproducibly led to rather similar nanopore sizes (5.07 ± 0.02, 5.13 ± 0.02, and 5.25 ± 0.01 nm), respectively. The GPS nanostructures were found to exhibit high ionic current rectification as well as surface-enhanced Raman scattering (SERS) activity due to the presence of nanopores and numerous "hot spots" among the cross-linked AuNPs on the surface of GPS. The rectification effect of the small nanopores was observed even under high concentration of electrolyte (290 mM), along with SERS enhancement factors well above 1 × 105. The GPS nanostructures were successfully applied for SERS-based detection of glutathione from a single HeLa cell.

Nanopipette-Based SERS Aptasensor for Subcellular Localization of Cancer Biomarker in Single Cells.

Single cell analysis is essential for understanding the heterogeneity, behaviors of cells, and diversity of target analyte in different subcellular regions. Nucleolin (NCL) is a multifunctional protein that is markedly overexpressed in most of the cancer cells. The variant expression levels of NCL in subcellular regions have a marked influence on cancer proliferation and treatments. However, the specificity of available methods to identify the cancer biomarkers is limited because of the high level of subcellular matrix effect. Herein, we proposed a novel technique to increase both the molecular and spectral specificity of cancer diagnosis by using aptamers affinity based portable nanopipette with distinctive surface-enhanced Raman scattering (SERS) activities. The aptamers-functionalized gold-coated nanopipette was used to capture target, while p-mercaptobenzonitrile (MBN) and complementary DNA modified Ag nanoparticles (AgNPs) worked as Raman reporter to produce SERS signal. The SERS signal of Raman nanotag was lost upon NCL capturing via modified DNA aptamers on nanoprobe, which further helped to verify the specificity of nanoprobe. For proof of concept, NCL protein was specifically extracted from different cell lines by aptamers modified SERS active nanoprobe. The nanoprobes manifested specifically good affinity for NCL with a dissociation constant Kd of 36 nM and provided a 1000-fold higher specificity against other competing proteins. Furthermore, the Raman reporter moiety has a vibrational frequency in the spectroscopically silent region (1800-2300 cm-1) with a negligible matrix effect from cell analysis. The subcellular localization and spatial distribution of NCL were successfully achieved in various types of cells, including MCF-7A, HeLa, and MCF-10A cells. This type of probing technique for single cell analysis could lead to the development of a new perspective in cancer diagnosis and treatment at the cellular level.

Insight into Ion Transfer through the Sub-Nanometer Channels in Zeolitic Imidazolate Frameworks.

A crack-free sub-nanometer composite structure for the study of ion transfer was constructed by in situ growth of ZIF-90 [Zn(ICA)2 , ICA=Imidazole-2-carboxaldehyde] on the tip of a glass nanopipette. The potential-driven ion transfer through the sub-nanometer channels in ZIF-90 is strongly influenced by the pH of the solution. A rectification ratio over 500 is observed in 1 m KCl solution under alkaline conditions (pH 11.58), which is the highest value reported under such a high salt concentration. Fluorescence experiments show the super-high rectification ratio under alkaline conditions results from the strong electrostatic interaction between ions and the sub-nanometer channels of ZIF-90. In addition to providing a general pathway for further study of mass-transfer process through sub-nanometer channels, the approach enable all kinds of metal-organic frameworks (MOFs) to be used as ionic permselectivity materials in nanopore-based analysis.

Organic Cyanide Decorated SERS Active Nanopipettes for Quantitative Detection of Hemeproteins and Fe3+ in Single Cells.

It is challenging to develop a robust nanoprobe for real-time operational and accurate detection of heavy metals in single cells. Fe-CN coordination chemistry has been well studied to determine the structural characteristics of hemeproteins by different techniques. However, the frequently used cyanide ligands are inorganic molecules that release cyanide anion under particular conditions and cause cyanide poisoning. In the present study, organic cyanide (4-mercaptobenzonitrile, MBN) was utilized for the first time in developing a facile nanoprobe based on surface-enhanced Raman scattering (SERS) for quantitative detection of hemeproteins (oxy-Hb) and trivalent iron (Fe3+) ions. The nanoprobe prepared by coating the glass capillary tip (100 nm) with a thin gold film, which enables highly localized study in living cell system. The cyanide stretching vibration in MBN was highly sensitive and selective to Fe3+ and oxy-Hb with excellent binding affinity (Kd 0.4 pM and 0.1 nM, respectively). The high sensitivity of the nanoprobe to analyte (Fe3+) was attributed to the two adsorption conformations (-SH and -CN) of MBN to the gold surface. Therefore, MBN showed an exceptional dual-peak (2126 and 2225 cm-1) behavior. Furthermore, the special Raman peaks of cyanide in 2100-2300 cm-1 (silent region of SERS spectra) are distinguishable from other biomolecules characteristic peaks. The selective detection of Fe3+ in both free and protein-bound states in aqueous solution is achieved with 0.1 pM and 0.08 µM levels of detection limits, respectively. Furthermore, practical applicability of fabricated nanoprobe was validated by detection of free Fe3+ in pretreated living HeLa cells by direct insertion of a SERS active nanoprobe. Regarding the appropriate precision, good reproducibility (relative standard deviation, RSD 7.2-7.6%), and recyclability (retain good Raman intensity even after three renewing cycles) of the method, the developed sensing strategy on a nanopipette has potential benefits for label-free, qualitative and quantitative recognition of heavy metal ions within nanoliter volumes.