Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1287998 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy based on live microorganisms has shown promise in preclinical studies, but its clinical translation has been hampered by limited efficacy and innegligible toxicity. Here, we developed M-BLAST (Macrophage-Bacteria encapsulation Lytic Autoactivated Synergistic Therapeutics), a dual-gated macrophage-mediated bacterial tumor-targeted delivery and in situ activation system. M-BLAST incorporates density-regulated virulence-enhanced attenuated Salmonella strains as the therapeutic core, thermally-controlled GSDMD-N-expressing macrophages as the delivery vector, and copper selenide, a photothermal material, as a heat-shock “primer.” Following systemic administration, localized near-infrared irradiation at the tumor site triggers macrophage pyroptosis, ensuring rapid and complete bacterial release. This disrupts the immunosuppressive tumor microenvironment and elicits a widespread cascading antitumor response just like a “immune bomb”, while dual-gating design of bacterial density and heat-shock ensures safety by preventing off-target activation in non-tumor regions. M-BLAST promises to enhance the therapeutic utility of living engineered bacteria for cancer while ensuring safety.
2025-12-19 | GSE291419 | GEO
Project description:Due to low numbers and poor accessibility of host cells that are targeted for effector delivery, the actual biological functions of most effectors remain elusive. Here, we developed a novel Isolation Nuclei TArgeted by Bacterial Effectors (INTABE) system, which facilitates selectively recovering nuclei of the cells in Arabidopsis thaliana plants that have received type-III effectors of pathogenic Xanthomonas bacteria. Using these nuclei as studying materials, we analysed changes in host gene expression and their correlation with changes in DNA methylation induced by Xanthomonas effector Outer Protein D (XopD).
2022-10-22 | E-MTAB-10281 | biostudies-arrayexpress
Project description:The probiotic strain Escherichia coli Nissle 1917 (EcN), a potential member of tumor-targeting bacteria, shows great promise for cancer treatment. By leveraging engineered EcN, we can design a bacteria-assisted, tumor-targeted therapy for the biosynthesis and targeted delivery of small-molecule anticancer agents. In this study, we aimed to use EcN as a base for synthesizing Romidepsin (FK228), an FDA-approved drug originally made by Chromobacterium violaceum No. 96. Through gene cluster reconstruction, promoter optimization, and genome modification, we created FK228-producing strains to boost anticancer efficacy. The engineered strain achieved a maximum in vitro yield of 1.5 mg/L. In 4T1 tumor-bearing BALB/c mouse xenograft models , six recombinant strains outperformed the wild-type EcN. Proteome showed that inflammatory response induced by EcN combined with intratumoral FK228 production improved treatment results. Also, targeted synthesis reduced FK228's cardiotoxicity and mortality. Engineered EcN enables drug biosynthesis and precise delivery, offering powerful anticancer activity.
2026-02-14 | PXD073783 | Pride
Project description:ntroduction: Recent studies have discovered lung cancer subtypes to have their own profile of microbiome within the tumor microenvironment. Additionally, the tumor associated microbiome exhibited altered bacterial pathways, suggesting that certain bacterial families are more fit to facilitate tumor progression than others. We believe that there exists a crosstalk between lung adenocarcinoma cells (LUAD) and bacterial cells. Methods and Materials: RNA-seq was performed on LUAD cell lines to understand the paracrine signaling effects that bacterial biomolecules have. From our RNA-seq data, we chose to investigate glycolysis by measuring glucose uptake and lactate production, investigate invasive potential through invasion assays, and measure EMT markers. As lipopolysaccharides (LPS) are found abundantly on the cell wall of gram-negative bacteria and can activate toll like receptor 4 (TLR4), we inhibited TLR4 with C34 to determine the relationship between TLR4 and the phenotypic changes. Finally, to gain a better understanding of the bacterial biomolecules leading to the changes observed, we treated our media with either RNAse, charcoal, or dialyzed molecules > 3kDa. Results and Discussion: From our RNA-seq data, we observed a total of 948 genes upregulated in the presence of E. coli biomolecules. Of the 948 upregulated genes observed in LUAD cell lines incubated in E. coli biomolecules, we witnessed increased expression of Hexokinase II, JUN proto-oncogene, and Snail Family Transcriptional Repressor 1. We verified the elevation of glycolytic enzymes through western blot and saw elevation of 2-deoxyglucose uptake and lactate production in LUAD cell lines incubated in E. coli biomolecules using scintillation counter and lactate luminescence assay, respectively. In addition to E. coli elevating glycolysis in LUAD cell lines, we also saw increase in invasive potential by Boyden chamber. Inhibition of TLR4 did not lead to decreasing the impact of E. coli biomolecules on glycolysis or invasive potential of LUAD. Modulating our E. coli supplemented media with either RNAse, dextran-coated charcoal, or using a spin column to remove biomolecules < 3kDa resulted in changes in HKII and Claudin protein expression. Overall, these findings indicate a direct relationship between E. coli and LUAD, wherein several well-known hallmarks of cancer are upregulated. Future studies would do well in investigating these molecules further and fully understanding the impact of a microbial shift in the tumor microenvironment.
2025-02-19 | GSE286573 | GEO
Project description:Due to low numbers and poor accessibility of host cells that are targeted for effector delivery, the actual biological functions of most effectors remain elusive. Here, we developed a novel Isolation Nuclei TArgeted by Bacterial Effectors (INTABE) system, which facilitates selectively recovering nuclei of the cells in Arabidopsis thaliana plants that have received type-III effectors of pathogenic Xanthomonas bacteria. Using these nuclei as studying materials, we analysed changes in host gene expression and their correlation with changes in DNA methylation induced by Xanthomonas effector Outer Protein D (XopD).
2022-10-22 | E-MTAB-10280 | biostudies-arrayexpress
Project description:Adeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapted an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs. We identified a naturally-evolved and serotype-specific interaction of AAV9 with human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density-lipoprotein-receptor-related-protein 6 (LRP6) interactions specific to engineered capsids that cross the blood-brain barrier in non-human primates upon intravenous administration. The unbiased cell microarray screening approach also allowed us to identify off-target tissue binding interactions of engineered brain-enriched AAVs that may inform vectors’ peripheral organ tropism and side effects. These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain.
2024-07-31 | PXD045380 | Pride
Project description:Primary human myeloid cells are promising candidates for immunotherapy, yet efficient and scalable technologies for genetic engineering and screening in these cells are limited. Here we present a virus-like particle (VLP)-based toolkit that delivers diverse CRISPR genome editing modalities to human monocytes, macrophages, and dendritic cells with high efficiency while preserving viability and innate immune responsiveness. VLP-mediated delivery of ribonucleoprotein payloads supports gene knockout, base editing, and epigenetic silencing. Furthermore, in combination with AAV-mediated donor delivery, this approach enables site-specific integration of large DNA sequences via homology-directed repair. We also developed SLICeVLP, a system combining sgRNA delivery via VPX-lentivirus with Cas9 protein delivery via engineered virus-like particles (eVLPs), and applied it to perform pooled loss-of-function screens and Perturb-seq in human macrophages. We uncovered regulators of TNF production and CD80 expression in human macrophages, converging on TNFAIP3 as a central regulator of inflammatory polarization. TNFAIP3 ablation promoted a pro-inflammatory cell state that is resistant to suppressive polarization, and augmented cytotoxicity in engineered HER2 CAR-macrophages. Taken together, this platform enables unbiased functional genomics in primary human myeloid cells, with direct implications for myeloid cell therapy design.
2026-04-10 | GSE327644 | GEO
Project description:Primary human myeloid cells are promising candidates for immunotherapy, yet efficient and scalable technologies for genetic engineering and screening in these cells are limited. Here we present a virus-like particle (VLP)-based toolkit that delivers diverse CRISPR genome editing modalities to human monocytes, macrophages, and dendritic cells with high efficiency while preserving viability and innate immune responsiveness. VLP-mediated delivery of ribonucleoprotein payloads supports gene knockout, base editing, and epigenetic silencing. Furthermore, in combination with AAV-mediated donor delivery, this approach enables site-specific integration of large DNA sequences via homology-directed repair. We also developed SLICeVLP, a system combining sgRNA delivery via VPX-lentivirus with Cas9 protein delivery via engineered virus-like particles (eVLPs), and applied it to perform pooled loss-of-function screens and Perturb-seq in human macrophages. We uncovered regulators of TNF production and CD80 expression in human macrophages, converging on TNFAIP3 as a central regulator of inflammatory polarization. TNFAIP3 ablation promoted a pro-inflammatory cell state that is resistant to suppressive polarization, and augmented cytotoxicity in engineered HER2 CAR-macrophages. Taken together, this platform enables unbiased functional genomics in primary human myeloid cells, with direct implications for myeloid cell therapy design.
2026-04-08 | GSE327133 | GEO
Project description:Primary human myeloid cells are promising candidates for immunotherapy, yet efficient and scalable technologies for genetic engineering and screening in these cells are limited. Here we present a virus-like particle (VLP)-based toolkit that delivers diverse CRISPR genome editing modalities to human monocytes, macrophages, and dendritic cells with high efficiency while preserving viability and innate immune responsiveness. VLP-mediated delivery of ribonucleoprotein payloads supports gene knockout, base editing, and epigenetic silencing. Furthermore, in combination with AAV-mediated donor delivery, this approach enables site-specific integration of large DNA sequences via homology-directed repair. We also developed SLICeVLP, a system combining sgRNA delivery via VPX-lentivirus with Cas9 protein delivery via engineered virus-like particles (eVLPs), and applied it to perform pooled loss-of-function screens and Perturb-seq in human macrophages. We uncovered regulators of TNF production and CD80 expression in human macrophages, converging on TNFAIP3 as a central regulator of inflammatory polarization. TNFAIP3 ablation promoted a pro-inflammatory cell state that is resistant to suppressive polarization, and augmented cytotoxicity in engineered HER2 CAR-macrophages. Taken together, this platform enables unbiased functional genomics in primary human myeloid cells, with direct implications for myeloid cell therapy design.
2026-04-08 | GSE327124 | GEO
Project description:Primary human myeloid cells are promising candidates for immunotherapy, yet efficient and scalable technologies for genetic engineering and screening in these cells are limited. Here we present a virus-like particle (VLP)-based toolkit that delivers diverse CRISPR genome editing modalities to human monocytes, macrophages, and dendritic cells with high efficiency while preserving viability and innate immune responsiveness. VLP-mediated delivery of ribonucleoprotein payloads supports gene knockout, base editing, and epigenetic silencing. Furthermore, in combination with AAV-mediated donor delivery, this approach enables site-specific integration of large DNA sequences via homology-directed repair. We also developed SLICeVLP, a system combining sgRNA delivery via VPX-lentivirus with Cas9 protein delivery via engineered virus-like particles (eVLPs), and applied it to perform pooled loss-of-function screens and Perturb-seq in human macrophages. We uncovered regulators of TNF production and CD80 expression in human macrophages, converging on TNFAIP3 as a central regulator of inflammatory polarization. TNFAIP3 ablation promoted a pro-inflammatory cell state that is resistant to suppressive polarization, and augmented cytotoxicity in engineered HER2 CAR-macrophages. Taken together, this platform enables unbiased functional genomics in primary human myeloid cells, with direct implications for myeloid cell therapy design.
2026-04-08 | GSE327357 | GEO