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Bioengineered Extracellular Vesicles Co-delivering PD-L1 and miR-27a-3p Synergistically Reprogram T cells To Treat Inflammatory Bowel Disease [scRNA-Seq]

ABSTRACT: Current treatments for inflammatory bowel disease (IBD) primarily rely on systemic immunosuppression, which often exhibits limited efficacy and off-target toxicity. Here we present a bioengineered extracellular vesicle (EV) platform designed for inflammatory bowel-targeted delivery of dual-action therapeutics, enabling precise modulation of T cell responses to enhance IBD treatment efficacy. EVs derived from Wharton’s jelly mesenchymal stem cells ( WJ-MSCs) were engineered to display membrane-bound PD-L1 and encapsulate miRNA 27a-3p (miR-27a-3p). The platform leverages WJ-MSCs’ intrinsic immunomodulatory properties and CXCR4-mediated recruitment to inflamed tissues. PD-L1 not only promotes immunosuppression of effector T cells, but also may enhance EV retention within inflamed sites. Meanwhile, miR-27a-3p shifts the Th17/Treg balance from a pro-inflammatory Th17 phenotype toward an anti-inflammatory Treg phenotype by targeting prohibitin 1. Bulk RNA sequencing of human CD4⁺ T cells treated with the EVs revealed downregulated of Th1/Th17-associated transcripts. In a humanized mouse model of colitis, EV treatment significantly reduced disease severity, diminished intestinal T cell infiltration, and restored mucosal integrity. Single-cell RNA sequencing demonstrated expansion of Treg cells and contraction of effector memory subsets, indicating durable immune modulation. This engineered EV platform represents a novel therapeutic paradigm that combines inflamed tissue targeting and dual immunomodulatory mechanisms to restore immune tolerance in IBD, addressing key limitations of conventional immunosuppressive approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302696 | GEO | 2025/11/12

REPOSITORIES: GEO

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Project description:Inflammatory bowel disease (IBD) is a complex multi-factorial inflammatory disease with Crohn’s disease (CD) and ulcerative colitis (UC) being the two most common forms. A number of transcriptional profiling studies have provided compelling evidence that describe the role of protein-coding genes and microRNAs in modulating the immune responses in IBD. In the present study, we performed a genome-wide transcriptome profiling of lncRNAs and protein-coding genes in inflamed and non-inflamed colon pinch biopsies from the IBD patients using expression microarrays platform. In this study, we identified widespread dysregulation of lncRNAs and protein-coding genes in both inflamed and non-inflamed CD and UC compared to the healthy controls. In case of inflamed CD and UC (iCD and iUC), we identified 438 and 745 differentially expressed lncRNAs, respectively, while in case of the non-inflamed CD and UC (niCD and niUC), we identified 12 and 19 differentially expressed lncRNAs, respectively. We also observed significant enrichment (p-value < 0.001, Pearson’s Chi-squared test) for 96 differentially expressed lncRNAs and 154 protein-coding genes within the IBD susceptibility loci. Furthermore, we found strong positive expression correlations for the intersecting and cis-neighboring differentially expressed IBD loci-associated lncRNA-protein-coding gene pairs. The functional annotation analysis of differentially expressed genes revealed that they are involved in immune response, pro-inflammatory cytokine activity and MHC protein complex. The lncRNA expression profiling in both inflamed and non-inflamed CD and UC, successfully stratified IBD patients from the healthy controls. Taken together, the identified lncRNA transcriptional signature along with clinically relevant parameters suggests their potential as biomarkers in IBD. A total of 96 biopsy samples (including 6 samples used as technical replicates) extracted from different colonic locations from 45 patients (CD=13, UC=20, Controls=12) were profiled using Agilent Custom 8x60K format lncRNA expression microarray. In Gencode v15 lncRNA microarray design, each lncRNA transcript is targeted by two probes covering 22,001 lncRNA transcripts corresponding to 12,963 lncRNA genes. In addition, each array contains 17,535 randomly-selected protein-coding targets, of which 15,182 (unique 12,787) correspond to protein-coding genes.

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Bioengineered Extracellular Vesicles Co-delivering PD-L1 and miR-27a-3p Synergistically Reprogram T cells To Treat Inflammatory Bowel Disease [scRNA-Seq]

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