Lactobacillus plantarum-Derived Extracellular Vesicles Modulate Macrophage Polarization and Gut Homeostasis for Alleviating Ulcerative Colitis.

Extracellular vesicles released by probiotics have been demonstrated to effectively alleviate intestinal inflammation, yet the precise underlying mechanisms remain unclear. In this research, for the first time, Lactobacillus plantarum UJS001 (LP-UJS) was isolated from fermented sauerkraut in Zhenjiang, China. Thereafter, the therapeutic effect of LP-UJS-derived extracellular vesicles (LP-UJS-EVs) on dextran sulfate sodium-induced ulcerative colitis (UC) in mice was analyzed to elucidate the immune mechanisms. According to our findings, LP-UJS-EVs played a pivotal role in restoring the intestinal barrier and alleviating intestinal inflammation. Notably, LP-UJS-EVs induced M2 polarization of macrophages, promoted the release of IL-10 and TGF-ß, inhibited the release of histamine, IL-6, and TNF-α, and exerted regulatory effects on intestinal microflora, as evidenced by the reduced abundances of Coprococcus, Parabacteroides, Staphylococcus, and Allobaculum, alongside the enhanced abundance of Prevotella. Furthermore, both LP-UJS and LP-UJS-EVs affected the lysine degradation pathway and significantly increased the abundance of related metabolites, especially oxoadipic acid. In summary, our results underscore the substantial therapeutic potential of LP-UJS and its secreted EVs in the treatment of UC.

Polydopamine nanoparticles cross-linked hyaluronic acid photothermal hydrogel with cascading immunoinducible effects for in situ antitumor vaccination.

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.

Lactate in the tumor microenvironment: A rising star for targeted tumor therapy.

Metabolic reprogramming is one of fourteen hallmarks of tumor cells, among which aerobic glycolysis, often known as the "Warburg effect," is essential to the fast proliferation and aggressive metastasis of tumor cells. Lactate, on the other hand, as a ubiquitous molecule in the tumor microenvironment (TME), is generated primarily by tumor cells undergoing glycolysis. To prevent intracellular acidification, malignant cells often remove lactate along with H+, yet the acidification of TME is inevitable. Not only does the highly concentrated lactate within the TME serve as a substrate to supply energy to the malignant cells, but it also works as a signal to activate multiple pathways that enhance tumor metastasis and invasion, intratumoral angiogenesis, as well as immune escape. In this review, we aim to discuss the latest findings on lactate metabolism in tumor cells, particularly the capacity of extracellular lactate to influence cells in the tumor microenvironment. In addition, we examine current treatment techniques employing existing medications that target and interfere with lactate generation and transport in cancer therapy. New research shows that targeting lactate metabolism, lactate-regulated cells, and lactate action pathways are viable cancer therapy strategies.

Cascade biomimetic intelligent nanotheranostic agents for imaging-guided tumor synergistic therapy.

Aim: Achieving drug-targeting delivery and environment-responsive releasing to realize imaging-guided precise tumor therapy. Materials & methods: Graphene oxide (GO) was used as the drug-delivery system to load indocyanine green (ICG) and doxorubicin (DOX) to form a GO/ICG&DOX nanoplatform, in which GO can quench the fluorescence of ICG and DOX. MnO2 and folate acid-functionalized erythrocyte membrane were further coated into the surface of GO/ICG&DOX to obtain an FA-EM@MnO2-GO/ICG&DOX nanoplatform. Results: The FA-EM@MnO2-GO/ICG&DOX nanoplatform has longer blood circulation time, precise targeting delivery to tumor tissues and catalase-like activity. Both in vitro and in vivo results demonstrated that the FA-EM@MnO2-GO/ICG&DOX nanoplatform has better therapeutic efficacy. Conclusion: The authors successfully fabricated a glutathione-responsive FA-EM@MnO2-GO/ICG&DOX nanoplatform, which can achieve drug-targeting delivery and precise drug release.

Extended Conjugation Tuning Carbon Nitride for Non-sacrificial H2 O2 Photosynthesis and Hypoxic Tumor Therapy.

Artificial photocatalysis offers a clean approach for producing H2 O2 . However, the poor selectivity and activity of H2 O2 production hamper traditional industrial applications and emerging photodynamic therapy (PDT)/chemodynamic therapy (CDT). Herein, we report a C5 N2 photocatalyst with a conjugated C=N linkage for selective and efficient non-sacrificial H2 O2 production in both normoxic and hypoxic systems. The strengthened delocalization of π-electrons by linkers in C5 N2 downshifted the band position, thermodynamically eliminating side H2 evolution reaction and kinetically promoting water oxidation. As a result, C5 N2 had a competitive solar-to-chemical conversion efficiency of 0.55 % in overall H2 O2 production and exhibited by far the highest activity under hypoxic conditions (698 µM h-1 ). C5 N2 was further applied to hypoxic PDT/CDT with outstanding performance in apparent cancer cell death and synchronous bioimaging. The study sheds light on the photosynthesis of H2 O2 by carbon nitrides for health applications.

AroC, a chorismate synthase, is required for the formation of Edwardsiella tarda biofilms.

Biofilms contribute to the resistance of Edwardsiella tarda to antibiotics and host immunity. AroC in the shikimate pathway produces chorismate to synthesize crucial intermediates such as indole. In this study, the differences between biofilms produced by aroC mutants (△aroC), wild-type (WT) strains, and △aroC complementary strains (C△aroC) were detected both in vitro with 96-well plates, tubes, or coverslips and in vivo using a mouse model of subcutaneous implants. When examining potential mechanisms, we found that the diameters of the movement rings in soft agar plates and the flagellar sizes and numbers determined by silver staining were all lower for △aroC than for WT and C△aroC. Moreover, qRT-PCR showed that the transcription levels of flagellar synthesis genes, fliA and fliC, were reduced in △aroC. AroC, FliC, or FliA may accompany the motility of △aroC strains. In addition, compared with the WT and C△aroC, the amounts of indole in △aroC were significantly decreased. Notably, the formation of biofilms by these strains could be promoted by exogenous indole. Therefore, the aroC gene could affect the biofilm formation of E. tarda concerning its impact on flagella and indole.

Biomimetic smart nanoplatform for dual imaging-guided synergistic cancer therapy.

Developing an integrated multimodal diagnosis and therapeutics nanoplatform is of great importance to enhance the outcome of cancer therapy. Herein, we report a highly efficient and biocompatible nanoplatform based on the assembly of a graphene oxide (GO) and metal-organic framework (MOF) Fe-porphyrin, which was coated with a folate-functionalized erythrocyte membrane (FA-EM@GO-MOF). The nanoplatform could be targeted to cancer cells precisely, and could avoid immune elimination and had prolonged blood circulation due to the presence of FA-EM on its surface. The presence of GO and paramagnetic Fe ions endowed the nanoplatform with robust fluorescence imaging and T2-weighted magnetic resonance imaging capacities. The porous structure and large surface area of GO-MOF make it desirable for drug delivery in chemotherapy. More importantly, with one operation, under the same laser (808 nm) irradiation, both photothermal therapy and photodynamic therapy could be triggered for efficient synergistic treatment by using MOF as a photosensitizer. This synergistic anticancer therapy promoted the generation of tumor-associated antigens and evoked an antitumor immune response. In vitro and in vivo therapy studies highlighted that the as-fabricated biomimetic nanoplatform for dual imaging-guided synergistic cancer therapy was highly effective yet straightforward, paving a new avenue for cancer diagnosis and therapy.

Facile Preparation of WO3-x Dots with Remarkably Low Toxicity and Uncompromised Activity as Co-reactants for Clinical Diagnosis by Electrochemiluminescence.

The exceptional nature of WO3-x dots has inspired widespread interest, but it is still a significant challenge to synthesize high-quality WO3-x dots without using unstable reactants, expensive equipment, and complex synthetic processes. Herein, the synthesis of ligand-free WO3-x dots is reported that are highly dispersible and rich in oxygen vacancies by a simple but straightforward exfoliation of bulk WS2 and a mild follow-up chemical conversion. Surprisingly, the WO3-x dots emerged as co-reactants for the electrochemiluminescence (ECL) of Ru(bpy)32+ with a comparable ECL efficiency to the well-known Ru(bpy)32+ /tripropylamine (TPrA) system. Moreover, compared to TPrA, whose toxicity remains a critical issue of concern, the WO3-x dots were ca. 300-fold less toxic. The potency of WO3-x dots was further explored in the detection of circulating tumor cells (CTCs) with the most competitive limit of detection so far.

Hyaluronic acid-modified mesoporous silica-coated superparamagnetic Fe3O4 nanoparticles for targeted drug delivery.

Introduction: The targeted delivery of anti-cancer drugs to tumor tissue has been recognized as a promising strategy to increase their therapeutic efficacy and reduce side effects. Mesoporous silica-coated superparamagnetic Fe3O4 nanoparticles (NH2-MSNs), a kind of nanocarrier, can passively enter tumor tissues to enhance the permeability and retention of drugs. However, NH2-MSNs do not specifically bind to cancer cells. This drawback encouraged us to develop a more efficient nanocarrier for cancer therapy. Methods: Herein, we describe the development of an effective nanocarrier based on NH2-MSNs, which were modified with hyaluronic acid on their surface (HA-MSNs) and loaded with doxorubicin (DOX). We have successfully fabricated uniform spherical HA-MSNs nanocarriers. The targeting ability of this delivery system was evaluated through specific uptake by cells and IVIS imaging. Results: DOX-HA-MSNs nanocarriers displayed more dramatic cytotoxic activity against 4T1 breast cancer cells compared to GES-1 gastric mucosa cells. In vivo results revealed that once DOX-HA-MSNs nanocarriers are exposed to an external magnetic field, they could be rapidly attracted to the magnet and effectively cross the cytoplasmic membrane via CD44 receptor-mediated transcytosis. This allows them to access the cancer cell cytoplasm and release DOX based on changes in the physiological environment. Both in vitro and in vivo results demonstrated that the HA-MSNs nanocarriers provided better therapeutic efficacy. Conclusion: The HA-MSNs nanocarriers represent an effective new paradigm to treat cancers due to active targeting to the tumor cells. Moreover, the specific uptake by the tumor effectively protects normal tissues to reduce off-target side effects. The reported findings support further investigation of HA-MSNs for cancer therapy.

EsR240, a non-coding sRNA, is required for the resistance of Edwardsiella tarda to stresses in macrophages and for virulence.

Bacterial small non-coding RNAs (sRNAs) are gene expression modulators that respond to environmental changes and pathogenic conditions. In this study, 13 novel sRNAs were identified in the intracellular pathogen, Edwardsiella tarda (E. tarda) ET13 strain, based on RNA sequencing and bioinformatic analyses. Eight of the 13 putative sRNAs from the ET13 strain were transcribed (as indicated by RT-PCR) following exposure to different stresses. The transcription levels of three sRNAs (EsR128, EsR139 and EsR240) were all highly induced under these stress conditions. Northern blot hybridization was employed to verify that EsR240 was expressed in the ET13 strain under both logarithmic and stationary growth phases, and that it formed a single copy transcript in the chromosomes of the ET13 strain. The precise start and end points of EsR240 were determined using 5'and 3' RACE. The conservation of EsR240 was in agreement with the characteristics of sRNA, as indicated by a BLAST analysis. Furthermore, the survival rates of EsR240 mutant were lower than the rates of the wild type ET13 under stress conditions. When the infection time was extended 4 or 6 h, the CFUs of the wild type bacteria increased more significantly within macrophages compared to the mutant. When the intra-peritoneal (i.p.) route of infection was used in mice, the bacterial loads of the tissues in the mice infected with the wild type bacteria were significantly higher than in the mice infected with the mutants. The virulence of the EsR240 mutant was 6.79-fold lower than the wild type bacterium based on the LD50. In addition, the IntaRNA program was used to predict the target genes of EsR240. Out of the top 10 predicted target genes, 9 genes were regulated by EsR240. These target genes may encode FtsH protease modulator YccA, Na+ and H+ antiporters, FtsX-like permease family protein, glycoside hydrolases or various other proteins. Therefore, EsR240 may positively regulate its target genes in E. tarda to maintain intracellular survival within host macrophages and to increase its virulence.

In situ fabrication of radiopaque microcapsules for oral delivery and real-time gastrointestinal tracking of Bifidobacterium.

INTRODUCTION: Although oral administration of Bifidobacterium is a promising approach for diseases, lack of resistance to harsh conditions and real-time tracking in gastrointestinal system in vivo are still major challenges in basic research and clinical applications. MATERIALS AND METHODS: In this study, we fabricated a chitosan-coated alginate microcapsule loaded with in situ synthesized barium sulfate (CA/BaSO4 microcapsule) for oral Bifidobacterium delivery and real-time X-ray computed tomography (CT) imaging. CA/BaSO4 microcapsules containing the Bifidobacterium were prepared in situ by one-step electrostatic spraying method, and then coated with chitosan. RESULTS: The results indicated that CA/BaSO4 microcapsules with an average diameter of approximately 200 µm possessed favorable mechanical stability and X-ray attenuation capacity. Encapsulation of Bifidobacteria in the CA/BaSO4 microcapsules exhibited superior resistance to cryopreservation and gastric acid environment in vitro. After oral administration in mice, these CA/BaSO4 microcapsules could be real-time visualized by CT imaging and readily reached the intestine to release Bifidobacteria. CONCLUSION: The radiopaque CA/BaSO4 microcapsules provide a novel platform for efficient protection, non-invasive real-time monitoring and intestinal-targeted Bifidobacterium delivery.

Biomineralization-Inspired Synthesis of Cerium-Doped Carbonaceous Nanoparticles for Highly Hydroxyl Radical Scavenging Activity.

Cerium oxide nanoparticles recently have received extensive attention in biomedical applications due to their excellent anti-oxidation performance. In this study, a simple, mild, and green approach was developed to synthesize cerium-doped carbonaceous nanoparticles (Ce-doped CNPs) using bio-mineralization of bull serum albumin (BSA) as precursor. The resultant Ce-doped CNPs exhibited uniform and ultrasmall morphology with an average size of 14.7 nm. XPS and FTIR results revealed the presence of hydrophilic group on the surface of Ce-doped CNPs, which resulted in excellent dispersity in water. The CCK-8 assay demonstrated that Ce-doped CNPs possessed favorable biocompatibility and negligible cytotoxicity. Using H2O2-induced reactive oxygen species (ROS) as model, Ce-doped CNPs showed highly hydroxyl radical scavenging capability. Furthermore, flow cytometry and live-dead staining results indicated that Ce-doped CNPs protected cells from H2O2-induced damage in a dose-dependent effect, which provided a direct evidence for anti-oxidative performance. These findings suggest that Ce-doped CNPs as novel ROS scavengers may provide a potential therapeutic prospect in treating diseases associated with oxidative stress.

Hyaluronic acid-functionalized bismuth oxide nanoparticles for computed tomography imaging-guided radiotherapy of tumor.

The inherent radioresistance and inaccuracy of localization of tumors weaken the clinical implementation effectiveness of radiotherapy. To overcome these limitations, hyaluronic acid-functionalized bismuth oxide nanoparticles (HA-Bi2O3 NPs) were synthesized by one-pot hydrothermal method for target-specific computed tomography (CT) imaging and radiosensitization of tumor. After functionalization with hyaluronic acid, the Bi2O3 NPs possessed favorable solubility in water and excellent biocompatibility and were uptaken specifically by cancer cells overexpressing CD44 receptors. The as-prepared HA-Bi2O3 NPs exhibited high X-ray attenuation efficiency and ideal radiosensitivity via synergizing X-rays to induce cell apoptosis and arrest the cell cycle in a dose-dependent manner in vitro. Remarkably, these properties offered excellent performance in active-targeting CT imaging and enhancement of radiosensitivity for inhibition of tumor growth. These findings demonstrated that HA-Bi2O3 NPs as theranostic agents exhibit great promise for CT imaging-guided radiotherapy in diagnosis and treatment of tumors.