Turning Waste into Wealth: A Potent Sono-Immune Strategy Based on Microcystis.

Currently, sonodynamic therapy (SDT) has limited therapeutic outcomes and immune responses, highlighting the urgent need for enhanced strategies that can stimulate robust and long-lasting antitumor effects. Microcystis, a notorious microalga, reveals the possibility of mediating SDT owing to the presence of gas vesicles (GVs) and phycocyanin (PC). Herein, a nontoxic strain of Microcystis elabens (labeled Me) is developed as a novel agent for SDT because it generates O2 under red light illumination, while GVs and PC act as cavitation nuclei and sonosensitizers, respectively. Moreover, algal debris is released after ultrasound irradiation, which primes the Toll-like receptor pathway to initiate a cascade of immune responses. This sono-immune strategy inhibits CT26 colon tumor growth largely by promoting dendritic cell maturation and cytotoxic T-cell activation. After combination with the immune checkpoint blockade, the therapeutic outcome is further amplified, accompanied by satisfactory abscopal and immune memory effects; similar potency is proven in the "cold" 4T1 triple-negative breast tumor. In addition, Me exhibit good biosafety without significant acute or chronic toxicity. Briefly, this study turns waste into wealth by introducing sono-immunotherapy based on Microcystis that achieved encouraging therapeutic effects on cancer, which is expected to be translated into the clinic. This article is protected by copyright. All rights reserved.

Constructing N-Containing Poly(p-Phenylene) (PPP) Films Through A Cathodic-Dehalogenation Polymerization Method.

Developing the films of N-containing unsubstituted poly(p-phenylene) (PPP) films for diverse applications is significant and highly desirable because the replacement of sp2 C atoms with sp2 N atoms will bring novel properties to the as-prepared polymers. In this research, an electrochemical-dehalogenation polymerization strategy is employed to construct two N-containing PPP films under constant potentials, where 2,5-diiodopyridine (DIPy) and 2,5-dibromopyrazine (DBPz) are used as starting agents. The corresponding polymers are named CityU-23 (for polypyridine) and CityU-24 (for polypyrazine). Moreover, it is found that both polymers can form films in situ on different conductive substrates (i.e., silicon, gold, ITO, and nickel), satisfying potential device fabrication. Furthermore, the as-obtained thin films of CityU-23 and CityU-24 exhibit good performance of alkaline hydrogen evolution reaction with the overpotential of 212.8 and 180.7 mV and the Tafel slope of 157.0 and 122.4 mV dec-1, respectively.

Association between intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid (n-3 PUFA DHA) and reduced risk of ovarian cancer: A systematic Mendelian Randomization study.

BACKGROUND & AIMS: Whether the intake of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, is beneficial for ovarian cancer (OC) remains controversial and we hope to disentangle this puzzle using genetic data from large-scale populations in European and Asian. METHODS: We employed, for the first time, a systematic Mendelian randomization (MR) design to comprehensively evaluate the causal effect of plasma DHA levels, an objective biomarker of DHA intake, on OC risk in European and then verified the extrapolation of the results in the Asian. Data in the analysis included genetic association data obtained from large-scale genome-wide association studies with 13,499 individuals for plasma DHA measurements and 66,450 individuals for OC in the European population, and 1361 individuals for plasma DHA measurements and 61,457 individuals for OC in the Asian population. The causal relationship between DHA and OC was estimated using the inverse-variance weighted approach, together with extensive validation and sensitivity analyses to verify the main results. RESULTS: In the European population, MR evidence suggested a causal relationship between higher plasma DHA levels and lower OC risk (OR, 0.89 for OC per one-SD increment in DHA; 95% CI, 0.83 to 0.96; P = 0.003). Subgroup analysis by histological type of OC indicated that this observed association was stronger among endometrioid ovarian cancer (EOC) (OR, 0.82; 95% CI, 0.69 to 0.96; P = 0.014). A similar causal association of borderline significance was reached in the Asian replication set. The above results were consistently supported by a series of validation and sensitivity analyses. CONCLUSION: Our study provided robust genetic evidence for a protective association between plasma DHA levels and lower risk of OC, especially EOC, in the European population. These findings may inform prevention strategies and interventions directed towards DHA intake and OC.

Ultrasmall iron-quercetin metal natural product nanocomplex with antioxidant and macrophage regulation in rheumatoid arthritis.

Oxidative stress, due to the disruption of the balance between reactive oxygen species (ROS) generation and the antioxidant defense system, plays an important role in the pathogenesis of rheumatoid arthritis (RA). Excessive ROS leads to the loss of biological molecules and cellular functions, release of many inflammatory mediators, stimulate the polarization of macrophages, and aggravate the inflammatory response, thus promoting osteoclasts and bone damage. Therefore, foreign antioxidants would effectively treat RA. Herein, ultrasmall iron-quercetin natural coordination nanoparticles (Fe-Qur NCNs) with excellent anti-inflammatory and antioxidant properties were constructed to effectively treat RA. Fe-Qur NCNs obtained by simple mixing retain the inherent ability to remove ROS of quercetin and have a better water-solubility and biocompatibility. In vitro experiments showed that Fe-Qur NCNs could effectively remove excess ROS, avoid cell apoptosis, and inhibit the polarization of inflammatory macrophages by reducing the activation of the nuclear factor-κ-gene binding (NF-κB) pathways. In vivo experiments showed that the swollen joints of mice with rheumatoid arthritis treated with Fe-Qur NCNs significantly improved, with Fe-Qur NCNs largely reducing inflammatory cell infiltration, increasing anti-inflammatory macrophage phenotypes, and thus inhibiting osteoclasts, which led to bone erosion. This study demonstrated that the new metal-natural coordination nanoparticles could be an effective therapeutic agent for the prevention of RA and other diseases associated with oxidative stress.

Chemical Modulation of Glucose Metabolism with a Fluorinated CaCO3 Nanoregulator Can Potentiate Radiotherapy by Programming Antitumor Immunity.

Tumor hypoxia and acidity are well-known features in solid tumors that cause immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional fluorinated calcium carbonate (fCaCO3) nanoregulator by coating CaCO3 nanoparticles with dopamine-grafted perfluorosebacic acid (DA2-PFSEA) and ferric ions by utilizing their coordination interaction. After PEGylation, the obtained fCaCO3-PEG showed high loading efficacy to perfluoro-15-crown-5-ether (PFCE), a type of perfluorocarbon with high oxygen solubility, thereby working as both oxygen nanoshuttles and proton sponges to reverse tumor hypoxia and acidity-induced resistance to radiotherapy. The as-prepared PFCE@fCaCO3-PEG could not only function as long-circulating oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment by restricting the production of lactic acid and reacting with extracellular protons. As a result, treatment with PFCE@fCaCO3-PEG could improve the therapeutic outcome of radiotherapy toward two murine tumors with distinct immunogenicity. The PFCE@fCaCO3-PEG-assisted radiotherapy could also collectively inhibit the growth of unirradiated tumors and reject rechallenged tumors by synergistically eliciting protective antitumor immunity. Therefore, our work presents the preparation of fluorinated CaCO3 nanoregulators to reverse tumor immunosuppression and potentiate radiotherapy through chemically modulating tumor hypoxic and acidic microenvironments tightly associated with tumor glucose metabolism.

Structural elucidation and anti-neuroinflammatory activity of Polygala tenuifolia polysaccharide.

Polygala tenuifolia is extensively used to treat amnesia in traditional Chinese medicine, and pharmacological studies have reported the beneficial effects of P. tenuifolia on intelligence and cognition. In the present study, the crude polysaccharide alkali-extracted from P. tenuifolia roots (PTB) inhibited lipopolysaccharide-induced microglia/astrocyte activation and significantly improved the learning and memory ability of Alzheimer's disease (AD) rats. To determine its bioactive components, a heteropolysaccharide (PTBP-1-3) was isolated from PTB. Structural analysis showed that PTBP-1-3 was composed of α-L-Araf-(1→, â†’3)-α-L-Araf-(1→, →5)-α-L-Araf-(1→, →3,5)-α-L-Araf-(1→, →2,5)-α-L-Araf-(1→, ß-D-Xylp-(1→, →2,3,4)-ß-D-Xylp-(1→, α-L-Rhap-(1→, ß-D-Galp-(1→, →4)-α-D-Galp-(1→, →6)-α-D-Galp-(1→, →6)-α-D-Glcp-(1→, →3,6)-α-D-Glcp-(1→, →6)-α-D-Manp-(1→, and →2,4)-ß-D-Manp-(1→ residues. PTBP-1-3 decreased the production of NO, TNF-α, and IL-1ß in lipopolysaccharide-activated BV2 microglia cells in a manner similar to that of minocycline. In conclusion, PTBP-1-3 exhibited a potent inhibitory effect on neuroinflammation, and could be one of the bioactive ingredients in PTB for anti-neuroinflammation. PTB and PTBP-1-3 may be potential therapeutic agents for the treatment of AD.

Titanium Sulfide Nanosheets Serve as Cascade Bioreactors for H2 S-Mediated Programmed Gas-Sonodynamic Cancer Therapy.

Gas-mediated sonodynamic therapy (SDT) has the potential to become an effective strategy to improve the therapeutic outcome and survival rate of cancer patients. Herein, titanium sulfide nanosheets (TiSX NSs) are prepared as cascade bioreactors for sequential gas-sonodynamic cancer therapy. TiSX NSs themselves as hydrogen sulfide (H2 S) donors can burst release H2 S gas. Following H2 S generation, TiSX NSs are gradually degraded to become S-defective and partly oxidized into TiOX on their surface, which endows TiSX NSs with high sonodynamic properties under ultrasound (US) irradiation. In vitro and in vivo experiments show the excellent therapeutic effects of TiSX NSs. In detail, large amounts of H2 S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H2 S gas also plays important roles in modulating and activating the immune system to effectively inhibit pulmonary metastasis. Finally, the metabolizable TiSX NSs are excreted out of the body without inducing any significant long-term toxicity. Collectively, this work establishes a cascade bioreactor of TiSX NSs with satisfactory H2 S release ability and excellent ROS generation properties under US irradiation for programmed gas-sonodynamic cancer therapy.

Copper-based nanomaterials for cancer theranostics.

Copper-based nanomaterials (Cu-based NMs) with favorable biocompatibility and unique properties have attracted the attention of many biomedical researchers. Cu-based NMs are one of the most widely studied materials in cancer treatment. In recent years, great progress has been made in the field of biomedicine, especially in the treatment and diagnosis of tumors. This review begins with the classification of Cu-based NMs and the recent synthetic strategies of Cu-based NMs. Then, according to the abundant and special properties of Cu-based NMs, their application in biomedicine is summarized in detail. For biomedical imaging, such as photoacoustic imaging, positron emission tomography imaging, and multimodal imaging based on Cu-based NMs are summarized, as well as strategies to improve the diagnostic effectiveness. Moreover, a series of unique structures and functions as well as the underlying property activity relationship of Cu-based NMs were shown to highlight their promising therapeutic performance. Cu-based NMs have been widely used in monotherapies, such as photothermal therapy (PTT) and chemodynamic therapy (CDT). Moreover, the sophisticated design in composition, structure, and surface fabrication of Cu-based NMs can endow these NMs with more modalities in cancer diagnosis and therapy. To further improve the efficiency of cancer treatment, combined therapy based on Cu-based NMs was introduced in detail. Finally, the challenges, critical factors, and future prospects for the clinical translation of Cu-based NMs as multifunctional theranostic agents were also considered and discussed. The aim of this review is to provide a better understanding and key consideration for the rational design of this increasingly important new paradigm of Cu-based NMs as theranostic agents. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Titanium carbide nanosheets with defect structure for photothermal-enhanced sonodynamic therapy.

Sonodynamic therapy (SDT) has attracted widespread interest in biomedicine, owing to its novel and noninvasive therapeutic method triggered by ultrasound (US). Herein, the Ti3C2 MXene nanosheets (Ti3C2 NSs) are developed as good sonosensitizers via a two-step method of chemical exfoliation and high-temperature treatment. With the high-temperature treatment, the oxygen defect of Ti3C2 MXene nanosheets (H-Ti3C2 NSs) is greatly increased. Therefore, the electron (e-) and hole (h+) generated by US can be separated faster due to the improved degree of oxidation, and then the recombination of e--h+ can be prevented with the abundant oxygen defect under US irradiation, which induced the sonodynamic efficiency greatly to improve around 3.7-fold compared with Ti3C2 NSs without high-temperature treatment. After PEGylation, the H-Ti3C2-PEG NSs show good stability and biocompatibility. In vitro studies exhibit that the inherent property of mild photothermal effect can promote the endocytosis of H-Ti3C2-PEG NSs, which can improve the SDT efficacy. In vivo studies further display that the increased blood supply by the mild photothermal effect can significantly relieve hypoxia in the tumor microenvironment, showing photothermal therapy (PTT) enhanced SDT. Most importantly, the H-Ti3C2-PEG NSs can be biodegraded and excreted out of the body, showing no significant long-term toxicity. Our work develops the defective H-Ti3C2 NSs as high-efficiency and safe sonosensitizers for photothermal-enhanced SDT of cancer, extending the biomedical application of MXene-based nanoplatforms.

Inorganic nanomaterials with rapid clearance for biomedical applications.

Inorganic nanomaterials that have inherently exceptional physicochemical properties (e.g., catalytic, optical, thermal, electrical, or magnetic performance) that can provide desirable functionality (e.g., drug delivery, diagnostics, imaging, or therapy) have considerable potential for application in the field of biomedicine. However, toxicity can be caused by the long-term, non-specific accumulation of these inorganic nanomaterials in healthy tissues, preventing their large-scale clinical utilization. Over the past several decades, the emergence of biodegradable and clearable inorganic nanomaterials has offered the potential to prevent such long-term toxicity. In addition, a comprehensive understanding of the design of such nanomaterials and their metabolic pathways within the body is essential for enabling the expansion of theranostic applications for various diseases and advancing clinical trials. Thus, it is of critical importance to develop biodegradable and clearable inorganic nanomaterials for biomedical applications. This review systematically summarizes the recent progress of biodegradable and clearable inorganic nanomaterials, particularly for application in cancer theranostics and other disease therapies. The future prospects and opportunities in this rapidly growing biomedical field are also discussed. We believe that this timely and comprehensive review will stimulate and guide additional in-depth studies in the area of inorganic nanomedicine, as rapid in vivo clearance and degradation is likely to be a prerequisite for the future clinical translation of inorganic nanomaterials with unique properties and functionality.

Bioorthogonal Coordination Polymer Nanoparticles with Aggregation-Induced Emission for Deep Tumor-Penetrating Radio- and Radiodynamic Therapy.

Radiodynamic therapy (RDT), an emerging therapeutic approach for cancer treatment by employing ionizing irradiation to induce localized photodynamic therapy (PDT) can overcome the drawbacks of the limited penetration depth for traditional PDT and the unconcentrated energy in the tumor for traditional radiotherapy (RT). Taking advantage of aggregation-induced emission (AIE) photosensitizers with bright fluorescence and efficient singlet oxygen production in the aggregate state, Hf-AIE coordination polymer nanoparticles (CPNs), which show both strong RT and RDT effect under X-ray irradiation, are developed. Furthermore, to enhance the tumor accumulation and prolong the tumor retention of the CPNs, bioorthogonal click chemistry is applied in the system through coupling between dibenzocyclooctyne (DBCO)-modified CPNs (Hf-AIE-PEG-DBCO) (PEG: poly(ethylene glycol)) and azide groups on the cell membrane formed by metabolic glycoengineering. Thanks to the high penetration of X-ray irradiation, the bioorthogonal-assisted RT and RDT combination therapy realizes significant killing of cancer cells without showing noticeable biotoxicity after intravenous administration of CPNs.

Perfluorocarbon nanodroplets stabilized with cisplatin-prodrug-constructed lipids enable efficient tumor oxygenation and chemo-radiotherapy of cancer.

Concurrent chemo-radiotherapy has been widely applied for the treatment of a wide range of cancers, but its therapeutic efficacy against most solid tumors is severely impaired by their intrinsic hypoxic microenvironments. Utilizing the high oxygen loading capacity of perfluoro-15-crown-5-ether (PFCE), herein, we prepare PFCE nanodroplets with cisplatin prodrug (cisPt(iv)) conjugated phospholipids and other commercial lipids as the stabilizer to enable tumor targeted oxygen shuttling. The obtained PFCE@cisPt(iv)-Lip shows high physiological stability and efficient oxygen loading capacity. As vividly visualized under an in vivo photoacoustic imaging system, tumors on the mice with intravenous injection of such PFCE@cisPt(iv)-Lip show effective tumor oxygenation. Together with X-ray exposure, such PFCE@cisPt(iv)-Lip upon intravenous injection could induce severe DNA damage of cells, thereby remarkably suppressing the tumor growth and significantly prolonging their survival time without causing obvious toxic side effects. This work highlights PFCE@cisPt(iv)-Lip as an adjuvant nanomedicine for enhanced chemo-radiotherapy of tumors by attenuating hostile tumor hypoxia, indicating its promising potential for future clinical translation ascribed to its straightforward synthesis and notable tumor growth inhibition at a safe dose.

Biodegradable Nickel Disulfide Nanozymes with GSH-Depleting Function for High-Efficiency Photothermal-Catalytic Antibacterial Therapy.

Bacterial infections caused by pathogens have always been a thorny issue that threatens human health, and there is urgent need to develop a new generation of antimicrobial nano-agents and treatments. Herein, biodegradable nickel disulfide (ND) nanozymes as excellent antibacterial agents that integrate excellent photothermal performance, nano-catalysis property, and glutathione (GSH)-depleting function have been successfully constructed. The ND nanozymes can effectively catalyze the decomposition of H2O2 to produce ⋅OH, and the hyperthermia of ND nanozymes generated by photothermal therapy (PTT) can further increase its catalytic activity, which provides rapid and effective bacterial killing effect compared with nano-catalytic treatment or PTT alone. Surprisingly, the ND nanozymes have the ability of GSH consumption, thus enhancing its sterilization effect. Moreover, the ND nanozymes are biodegradable nanomaterials that do not cause any significant toxicity in vivo. Collectively, the ND nanozymes with excellent photothermal performance, catalytic activity, and GSH-depleting function are used for high-efficiency sterilization.

Ultrafine Titanium Monoxide (TiO1+x) Nanorods for Enhanced Sonodynamic Therapy.

Ultrasound (US)-triggered sonodynamic therapy (SDT) that enables noninvasive treatment of large internal tumors has attracted widespread interest. For improvement in the therapeutic responses to SDT, more effective and stable sonosensitizers are still required. Herein, ultrafine titanium monoxide nanorods (TiO1+x NRs) with greatly improved sono-sensitization and Fenton-like catalytic activity were fabricated and used for enhanced SDT. TiO1+x NRs with an ultrafine rodlike structure were successfully prepared and then modified with polyethylene glycol (PEG). Compared to the conventional sonosensitizer, TiO2 nanoparticles, the PEG-TiO1+x NRs resulted in much more efficient US-induced generation of reactive oxygen species (ROS) because of the oxygen-deficient structure of TiO1+x NR, which predominantly serves as the charge trap to limit the recombination of US-triggered electron-hole pairs. Interestingly, PEG-TiO1+x NRs also exhibit horseradish-peroxidase-like nanozyme activity and can produce hydroxyl radicals (•OH) from endogenous H2O2 in the tumor to enable chemodynamic therapy (CDT). Because of their efficient passive retention in tumors post intravenous injection, PEG-TiO1+x NRs can be used as a sonosensitizer and CDT agent for highly effective tumor ablation under US treatment. In addition, no significant long-term toxicity of PEG-TiO1+x NRs was found for the treated mice. This work highlights a new type of titanium-based nanostructure with great performance for tumor SDT.

Engineered Cell-Derived Microparticles Bi2Se3/DOX@MPs for Imaging Guided Synergistic Photothermal/Low-Dose Chemotherapy of Cancer.

Cell-derived microparticles, which are recognized as nanosized phospholipid bilayer membrane vesicles, have exhibited great potential to serve as drug delivery systems in cancer therapy. However, for the purpose of comprehensive therapy, microparticles decorated with multiple therapeutic components are needed, but effective engineering strategies are limited and still remain enormous challenges. Herein, Bi2Se3 nanodots and doxorubicin hydrochloride (DOX) co-embedded tumor cell-derived microparticles (Bi2Se3/DOX@MPs) are successfully constructed through ultraviolet light irradiation-induced budding of parent cells which are preloaded with Bi2Se3 nanodots and DOX via electroporation. The multifunctional microparticles are obtained with high controllability and drug-loading capacity without unfavorable membrane surface destruction, maintaining their excellent intrinsic biological behaviors. Through membrane fusion cellular internalization, Bi2Se3/DOX@MPs show enhanced cellular internalization and deepened tumor penetration, resulting in extreme cell damage in vitro without considering endosomal escape. Because of their distinguished photothermal performance and tumor homing target capability, Bi2Se3/DOX@MPs exhibit admirable dual-modal imaging capacity and outstanding tumor suppression effect. Under 808 nm laser irradiation, intravenous injection of Bi2Se3/DOX@MPs into H22 tumor-bearing mice results in remarkably synergistic antitumor efficacy by combining photothermal therapy with low-dose chemotherapy in vivo. Furthermore, the negligible hemolytic activity, considerable metabolizability, and low systemic toxicity of Bi2Se3/DOX@MPs imply their distinguished biocompatibility and great potential for tumor theranostics.

Nanoparticle-Embedded Electrospun Fiber-Covered Stent to Assist Intraluminal Photodynamic Treatment of Oesophageal Cancer.

Drug-eluting stents (DESs) are promising candidates for treating human oesophageal cancer. However, the use of DESs to assist photodynamic therapy (PDT) of orthotopic oesophageal tumors is not yet demonstrated to the best of current knowledge. Herein, through an electrospinning technology it is shown that oxygen-producing manganese dioxide nanoparticles are embedded into elelctrospun fibers, which are subsequently covered onto stents. Upon implantation, the nanoparticles are gradually released from the fibers and then diffuse into the nearby tumor tissue. Then, the hypoxic microenvironment can be effectively alleviated by reaction of MnO2 with the endogenous H2 O2 within the tumor. After demonstrating the excellent PDT efficacy of the stents in a conventional subcutaneous mouse tumor model, such stents are further used for PDT treatment in a rabbit orthotopic oesophageal cancer model by inserting an optical fiber into the tumor site. Greatly prolonged survival of rabbits is observed after such intraluminal PDT treatment. Taken together, this work shows that the fiber-covered stent as a nanoparticle delivery platform can enable effective PDT as a noninvasive treatment method for patients with advanced-stage oesophageal cancer.

NaCeF4:Gd,Tb Scintillator as an X-ray Responsive Photosensitizer for Multimodal Imaging-Guided Synchronous Radio/Radiodynamic Therapy.

Photosensitizers (PSs) that are directly responsive to X-ray for radiodynamic therapy (RDT) with desirable imaging abilities have great potential applications in cancer therapy. Herein, the cerium (Ce)-doped NaCeF4:Gd,Tb scintillating nanoparticle (ScNP or scintillator) is first reported. Due to the sensitization effect of the Ce ions, Tb ions can emit fluorescence under X-ray irradiation to trigger X-ray excited fluorescence (XEF). Moreover, Ce and Tb ions can absorb the energy of secondary electrons generated by X-ray to produce reactive oxide species (ROS) for RDT. With the intrinsic absorption of X-ray by lanthanide elements, the NaCeF4:Gd,Tb ScNPs also act as a computed tomography (CT) imaging contrast agent and radiosensitizers for radiotherapy (RT) sensitization synchronously. Most importantly, the transverse relaxation time of Gd3+ ions is shortened due to the doping of Ce and Tb ions, leading to the excellent performance of our ScNPs in T2-weighted MR imaging for the first time. Both in vitro and in vivo studies verify that our synthesized ScNPs have good performance in XEF, CT, and T2-weighted MR imaging, and a synchronous RT/RDT is achieved with significant suppression on tumor progression under X-ray irradiation. Importantly, no systemic toxicity is observed after intravenous injection of ScNPs. Our work highlights that ScNPs have potential in multimodal imaging-guided RT/RDT of deep tumors.

Stress Granule Formation is One of the Early Antiviral Mechanisms for Host Cells Against Coxsackievirus B Infection.

Stress granules (SGs) are intracellular granules formed when cellular translation is blocked and have been reported to be involved in a variety of viral infections. Our previous studies revealed that SGs are involved in the coxsackievirus B (CVB) infection process, but the role of SGs in CVB infection has not been fully explored. In this study, we found that CVB type 3 (CVB3) could induce SG formation in the early phase of infection. Results showed that levels of CVB3 RNA and protein were significantly inhibited during the early stage of CVB3 infection by the elevated formation of SGs, while viral RNA and protein synthesis were significantly promoted when SG formation was blocked. Our findings suggest that SG formation is one of the early antiviral mechanisms for host cells against CVB infection.

Albumin-assisted exfoliated ultrathin rhenium disulfide nanosheets as a tumor targeting and dual-stimuli-responsive drug delivery system for a combination chemo-photothermal treatment.

Herein, we prepared an ultrathin rhenium disulfide nanosheet (utReS2) through the bovine serum albumin (BSA)-assisted ultrasonic exfoliation method, which showed great biocompatibility and high near-infrared (NIR) absorbance. The large surface specific area and the presence of BSA facilitate a high loading ratio and modification of multifunctional molecules. The low solubility anti-cancer drug resveratrol (RSV) was loaded onto the utReS2 surface to form a biocompatible nanocomposite (utReS2@RSV). A targeting molecule, folic acid (FA), was then conjugated to the BSA molecule of utReS2@RSV, resulting in utReS2@RSV-FA. The utReS2@RSV-FA exhibited a photothermal effect under an 808 nm laser irradiation. At pH = 6.5, about 16.5% of the RSV molecules was released from utReS2@RSV-FA over 24 h, while the value reached 55.3% after six cycles of NIR irradiation (5 min, 1 W cm-2). In vitro experiments of utReS2@RSV-FA showed that it had low cytotoxicity and an excellent HepG2 cells targeting effect. Upon pH/temperature dual-stimuli, utReS2@RSV-FA showed an enhanced cytotoxic effect. In vivo experiments of utReS2@RSV-FA intravenously injected into tumor-bearing mice showed that at 24 h post-injection, it could actively target and was largely accumulated in tumor tissue. When the injection was further accompanied by three cycles of NIR irradiation for 5 min, once a day, the tumor was efficiently suppressed, without relapse after 30 days. These findings demonstrate that utReS2@RSV-FA has a remarkable targeting ability while providing a dual-stimuli-responsive drug delivery system, and could effectively be used in a combination chemo-photothermal cancer treatment.

From the Cover: Potentiation of Drug-Induced Phospholipidosis In Vitro through PEGlyated Graphene Oxide as the Nanocarrier.

Cationic amphiphilic drugs (CADs) are small molecules that can induce phospholipidosis (PLD), causing the intracellular accumulation of phospholipid in the lamellar bodies. Nanotechnology based drug delivery systems have been used widely, while it is unknown if drug-induced PLD (DIP) can be potentiated through drug retention by indigestible nanocarriers. Due to the high drug loading capacity of graphene, we investigated if PEGylated graphene oxide (PEG-GO) loaded with CAD could potentiate DIP. Tamoxifen induced the accumulation of NBD-PE, a fluorescence labeled phospholipid in human hepatoma HepG2 cells, while PEG-GO loaded with tamoxifen (PEG-GO/tamoxifen) further potentiated PLD. PEG-GO/tamoxifen induced more gene expression of PLD marker than tamoxifen alone. PEG-GO enhanced DIP was also observed for other CAD, indicating that nanocarrier potentiated DIP could be universal. More lamellar bodies were observed in PEG-GO/tamoxifen treated cells than tamoxifen alone by transmission electron microscopy. When compared with tamoxifen alone, PEG-GO/tamoxifen showed a delayed but potent PLD. In addition, the retarded PLD recovery by PEG-GO/tamoxifen indicated that the reversibility of DIP was interfered. Confocal microscopy revealed the increased number of lysosomes, greater expression of lysosomal associated membrane protein 2 (LAMP2) (a PLD marker), and an increase in the co-localization between lysosome/LAMP2 and NBD-PE by PEG-GO/tamoxifen rather than tamoxifen alone. Finally, we found that PEG-GO or/and tamoxifen-induced PLD seemed to have no correlation with autophagy. This research suggests pharmaceutical companies and regulatory agencies that if nanoparticles are used as the vectors for drug delivery, the adverse drug effects may be further potentiated probably through the long-term accumulation of nanocarriers.