Chimeric Exosomes Functionalized with STING Activation for Personalized Glioblastoma Immunotherapy.

A critical challenge of existing cancer vaccines is to orchestrate the demands of antigen-enriched furnishment and optimal antigen-presentation functionality within antigen-presenting cells (APCs). Here, a complementary immunotherapeutic strategy is developed using dendritic cell (DC)-tumor hybrid cell-derived chimeric exosomes loaded with stimulator of interferon genes (STING) agonists (DT-Exo-STING) for maximized tumor-specific T-cell immunity. These chimeric carriers are furnished with broad-spectrum antigen complexes to elicit a robust T-cell-mediated inflammatory program through direct self-presentation and indirect DC-to-T immunostimulatory pathway. This chimeric exosome-assisted delivery strategy possesses the merits versus off-the-shelf cyclic dinucleotide (CDN) delivery techniques in both the brilliant tissue-homing capacity, even across the intractable blood-brain barrier (BBB), and the desired cytosolic entry for enhanced STING-activating signaling. The improved antigen-presentation performance with this nanovaccine-driven STING activation further enhances tumor-specific T-cell immunoresponse. Thus, DT-Exo-STING reverses immunosuppressive glioblastoma microenvironments to pro-inflammatory, tumoricidal states, leading to an almost obliteration of intracranial primary lesions. Significantly, an upscaling option that harnesses autologous tumor tissues for personalized DT-Exo-STING vaccines increases sensitivity to immune checkpoint blockade (ICB) therapy and exerts systemic immune memory against post-operative glioma recrudesce. These findings represent an emerging method for glioblastoma immunotherapy, warranting further exploratory development in the clinical realm.

Bacteria-Based Backpacks to Enhance Adoptive Macrophage Transfer against Solid Tumors.

Adoptive cell therapy has emerged as a promising approach for cancer treatment. However, the transfer of macrophages exhibits limited efficacy against solid tumors due to the dynamic cellular phenotypic shift from antitumor to protumor states within the immunosuppressive tumor microenvironment. In this study, a strategy of attaching bacteria to macrophages (Mø@bac) is reported that endows adoptively infused macrophages with durable stimulation by leveraging the intrinsic immunogenicity of bacteria. These attached bacteria, referred to as backpacks, are encapsulated with adhesive nanocoatings and can sustainably control the cellular phenotypes in vivo. Moreover, Mø@bac can repolarize endogenous tumor-associated macrophages, leading to a more robust immune response and thus reducing the tumor progression in a murine 4T1 cancer model without any side effects. This study utilizing bacteria as cellular backpacks opens a new avenue for the development of cell therapies.

Engineering cancer cell membranes with endogenously upregulated HSP70 as a reinforced antigenic repertoire for the construction of material-free prophylactic cancer vaccines.

Immune cells distinguish cancer cells mainly relying on their membrane-membrane communication. The major challenge of cancer vaccines exists in difficult identification of cancer neoantigens and poor understanding over immune recognition mechanisms against cancer cells, particularly the combination among multiple antigens and the cooperation between antigens and immune-associated proteins. We exploit cancer cell membranes as the whole cancer antigen repertoire and reinforce its immunogenicity by cellular engineering to modulate the cytomembrane's immune-associated functions. This study reports a vaccine platform based on radiation-engineered cancer cells, of which the membrane HSP70 protein as the immune chaperon/traitor is endogenously upregulated. The resulting positive influences are shown to cover immunogenic steps occurring in antigen-presenting cells, including the uptake and the cross-presentation of the cancer antigens, thus amplifying cancer-specific immunogenicity. Membrane vaccines offer chances to introduce desired metal ions through membrane-metal complexation. Using Mn2+ ion as the costimulatory interferon genes agonist, immune activity is enhanced to further boost adaptive cancer immunogenicity. Results have evidenced that this artificially engineered membrane vaccine with favorable bio-safety could considerably reduce tumorigenicity and inhibit tumor growth. This study provides a universally applicable and facilely available cancer vaccine platform by artificial engineering of cancer cells to inherit and amplify the natural merits of cancer cell membranes. STATEMENT OF SIGNIFICANCE: The major challenge of cancer vaccines exists in difficult identification of cancer neoantigens and poor understanding over immune recognition mechanisms against cancer cells, particularly the combination among multiple antigens and the cooperation between antigens and immune-associated proteins. Cancer cell membrane presents superior advantages as the whole cancer antigen repertoire, including the reported and the unidentified antigens, but its immunogenicity is far from satisfactory. Cellular engineering approaches offer chances to endogenously modulate the immune-associated functions of cell membranes. Such a reinforced vaccine based on the engineered cancer cell membranes matches better the natural immune recognition pathway than the conventional vaccines.

Deciphering the molecular mechanisms of Maxing Huoqiao Decoction in treating pulmonary fibrosis via transcriptional profiling and circRNA-miRNA-mRNA network analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung condition with unknown etiology and high mortality. Chinese herbal medicine has been used for more than a thousand years to treat various lung diseases. PURPOSE: The current study aimed to examine whether Chinese herbal Maxing Huoqiao Decoction (MXHQD) exerts therapeutic effects on IPF and to further uncover its underlying molecular mechanisms. METHODS: Mouse model of acute lung injury (ALI) or IPF was induced by intratracheal instillation of LPS or bleomycin, respectively. ALI mice were treated with MXHQD for 7 days, and lung tissues were taken for test after modeling 24 h. IPF mice were gavaged for 21 days after modeling. Lung tissues were subjected to whole transcriptome detection, and the differential RNAs were experimentally verified. RESULTS: The results showed that MXHQD alleviated the computed tomography (CT) and the pathological degree changes in mice with IPF, improved changes in the expression of fibrosis related genes and reduced the hydroxyproline expression in IPF mice. MXHQD also decreased the cell numbers in bronchoalveolar lavage fluids, and the expression levels of the inflammatory factors in the ALI mice lung tissues were significantly inhibited. By applying whole transcriptome analysis, results showed that MXHQD acted on 40 mRNAs, 15 miRNAs, 25 novel lncRNAs and 17 circRNAs to resist pulmonary fibrosis. The competing endogenous RNA (ceRNA) network diagram showed that the multiple components of MXHQD against fibrosis through a network of multiple targets. The differential mRNAs were mainly related to the innate immune response and the defense response to virus. Then the expression of mRNAs in the differential mRNA-miRNA-differential circRNA network in the lung tissue of IPF was verified. The expression of ZBP1 and ISG15 related to immune system and anti virus was verified at both gene and protein expressions. MXHQD could significantly inhibit the elevation of ZBP1 and ISG15 factors induced by the fibrosis model. CONCLUSION: Overall, our findings provide compelling evidence that MXHQD can alleviate IPF by modulating innate immunity. This is the first study to reveal the molecular mechanism underlying the multi-components, multi-channels and multi-targets anti-IPF immune injury of MXHQD, and supports its potential clinical application for IPF.

Reproductive outcomes of women with moderate to severe intrauterine adhesions after transcervical resection of adhesion: A systematic review and meta-analysis.

BACKGROUND: Intrauterine adhesions (IUA) refers to the adhesion of the inner wall of the uterus, resulting in complete or partial occlusion of the uterine cavity, which causes a series of symptoms. Transcervical resection of adhesion (TCRA) is the standard surgical method for patients with IUA. However, the recurrence rate of women with moderate to severe IUA is high and it has raised a big concern about the reproductive outcomes. METHODS: We conducted a scoping review by using 4 databases, including Google Scholar, PubMed, Scopus, Embase, and web of science, to retrieve relevant literature from September 1, 2001, to February 1, 2023, and to explore the reproductive outcomes in women with moderate to severe IUA after TCRA treatment. Following defined guidelines, data extraction was carried out by 2 researchers, and the findings were examined by 2 senior academics. The papers were evaluated by 2 reviewers using the inclusion and exclusion criteria. Using a form developed especially for this study, pertinent information was retrieved, including the first author, research design, study duration, age, intervention measurement, pregnancy rate, techniques of conception, and live birth rate. Two researchers conducted a quality assessment to determine any potential bias using the Cochrane technique and the Newcastle-Ottawa scale. RevMan 5.4.1 (The Cochrane Collaboration, London, United Kingdom) was used for data analysis, while I2 was used to evaluate heterogeneity. RESULTS: In total, this study included 2099 participants. After a detailed systematic review and meta-analyses, the results showed that pregnancy and live birth rates were increased significantly after TCRA, and the risk difference of the pregnancy rate was 1.75 [1.17, 2.62]. Besides, in 2 retrospective studies, the risk difference of live birth rate was 2.26, with a 95% confidence interval of 1.99 to 2.58. Moreover, the menstrual status of women also was improved, and the risk difference of hypermenorrhoea and amenorrhea were -0.28 [-0.37, -0.19] and -0.06 [0.26, 0.13], respectively. CONCLUSIONS: Taken together, TCRA is the useful strategy for the treatment of moderate to severe IUA to enhance the reproductive outcomes in women.

Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway.

Drug metabolizing enzymes (DMEs) and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC) is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE) on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2) cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(P)H: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate-cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant increase in the intracellular level of glutathione and total glutathione S-transferase content. SCE significantly elevated the messenger ribonucleic acid and protein levels of P-glycoprotein and multidrug resistance-associated protein 2 and 4, whereas the expression of organic anion transporting peptide 1A2 and 1B1 was significantly downregulated by SCE. Knockdown of Nrf2 by small interfering ribonucleic acid attenuated the regulatory effect of SCE on these DMEs and drug transporters. SCE significantly upregulated Nrf2 and promoted the translocation of Nrf2 from cytoplasm to the nuclei. Additionally, SCE significantly suppressed the expression of cytosolic Kelch-like ECH-associated protein 1 (the repressor of Nrf2) and remarkably increased Nrf2 stability in HepG2 cells. Taken together, our findings suggest that the hepatoprotective effects of SCE may be partially ascribed to the modulation of DMEs and drug transporters via Nrf2-mediated signaling pathway. SCE may alter the pharmacokinetics of other coadministered drugs that are substrates of these DMEs and transporters and thus cause unfavorable herb-drug interactions.