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Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

ABSTRACT: Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

PROVIDER: PRJNA757750 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15611524_1.fastq.gz	Fastqsanger.gz
	SRR15611524_2.fastq.gz	Fastqsanger.gz
	SRR15611525_1.fastq.gz	Fastqsanger.gz
	SRR15611525_2.fastq.gz	Fastqsanger.gz
	SRR15611526_1.fastq.gz	Fastqsanger.gz

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Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Project description:Oral rapamycin administration rapamycin is plagued by poor bioavailability and wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, numerous side effects and provides inadequate transplantation protection. Parental formulation was not possible due to rapamycin’s hydrophobicity (log P 4.3). Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)(PEG-b-PPS) polymersome (PS) nanocarriers modulates cellular biodistribution of rapamycin to change its immunosuppressive mechanism for enhanced efficacy while minimizing side effects. While oral rapamycin inhibits naïve T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) instead modulated Ly-6Clow monocytes and tolerogenic semi-mature dendritic cells, with immunosuppression mediated by CD8+ Tregs and rare CD4+ CD8+ double-positive T cells. As PEG-b-PPS PS are uniquely non-inflammatory, background immunostimulation from the vehicle was avoided, allowing immunomodulation to be primarily attributed to rapamycin’s cellular biodistribution. Repurposing mTOR inhibition significantly improved maintenance of normoglycemia in a clinically relevant, MHC-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of engineered nanocarriers to repurpose drugs for alternate routes of administration by rationally controlling cellular biodistribution.

2022-01-01 | GSE182776 | GEO

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability.

Project description: Not available

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RNA-sequencing analysis of aneurysmal tissues with or without treatment of targeted nanotherapy.

Project description:Our study represents the first detailed analysis of aneurysmal tissues with or without our targeted nanotherapy, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles.

2025-07-12 | GSE208025 | GEO

Comparative gene expression analysis of splenic T cells derived from rapamycin and PBS-treated mice

Project description:The macrolide rapamycin is known for its immunosuppressive properties since it inhibits mTOR (mammalian target of rapamycin), which activity affects differentiation and functions of various innate and adaptive immune cells involved in graft-versus-host disease development. Since rapamycin procures immunosuppressive effects on the immune response, rapamycin is an attractive candidate for graft-versus-host disease prevention after allogeneic bone marrow transplantation We used an MHC class I and II mismatched parent into F1 bone marrow transplantation mouse model to elucidate the mechanisms of rapamycin on T cells in the context of graft-versus-host disease prevention. To define the impact of rapamycin therapy on T cells gene expression profile, we performed mircoarray analysis and compared gene expression profiles of sorted splenic T cells from rapamycin and PBS treated mice

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Precision nanotherapy remodels the tumor-associated macrophage to reverse immunnosuppressive in pancreatic cancer.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive stroma rich in tumor-associated macrophages (TAMs) that limit the therapeutic efficacy. We introduce a TAM-targeted nanotherapy platform that selectively delivers either a CSF1R inhibitor or the STING agonist cGAMP to immunosuppressive TAMs. While CSF1R inhibitor–loaded nanoparticles efficiently depleted TAMs and produced moderate antitumor effects, TAM-targeted cGAMP nanoparticles reprogrammed TAMs into immune-stimulating effectors. This reprogramming normalized aberrant vasculature, alleviated desmoplasia, and enhanced infiltration and activation of cytotoxic immune cells. In combination with gemcitabine, PD-1 checkpoint blockade, or CAR-NK cell therapy, TAM-targeted STING activation provided an in situ immunostimulatory signal that markedly improved antitumor efficacy in preclinical PDAC models. Ex vivo efficacy in human PDAC tissues and a favorable safety profile show the translational potential of this TAM-targeted nanotherapy to overcome the immune desert of PDAC.

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Precision nanotherapy remodels the tumor-associated macrophage to reverse immunnosuppressive in pancreatic cancer [scRNA-seq]

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Comparative gene expression analysis of ex vivo isolated myeloid-derived suppressor cells (MDSCs) derived from rapamycin and PBS-treated mice

Project description:The macrolide rapamycin is known for its immunosuppressive properties since it inhibits mTOR (mammalian target of rapamycin), which activity affects differentiation and functions of various innate and adaptive immune cells involved in graft-versus-host disease development. Since rapamycin procures immunosuppressive effects on the immune response, rapamycin is an attractive candidate for graft-versus-host disease prevention after allogeneic bone marrow transplantation. Recently, an activating effect of rapamycin on the function of myeloid-derived suppressor cells (MDSCs), a subset of immune suppressive cells of myeloid origin was reported. However, the effect of rapamycin treatment on MDSCs induction and function in the management of graft-versus-host disease is largely unknown. We used an MHC class I and II mismatched parent into F1 bone marrow transplantation mouse model to elucidate the mechanisms of rapamycin on MDSCs in the context of graft-versus-host disease prevention. To define the impact of rapamycin therapy on MDSCs gene expression profile, we performed mircoarray analysis and compared gene expression profiles of ex vivo isolated MDSCs from rapamycin and PBS treated mice

2020-07-21 | GSE141414 | GEO

Rapamycin Immunomodulation Utilizes Time-Dependent Alterations of Lymph Node Architecture, Leukocyte Trafficking, and Gut Microbiome

Project description:Transplant recipients require lifelong, multimodal immunosuppression to prevent rejection by reducing alloreactive immunity. Rapamycin, a mechanistic target of rapamycin (mTOR) inhibitor, is known to modulate adaptive and innate immunity, while the full spectrum of its immunosuppressive mechanisms remains incompletely understood. Given the broad expression of mTOR, we investigated the understudied effects of rapamycin on lymph node (LN) architecture, leukocyte trafficking, and the gut microbiome and metabolism after 3, 7, and 30 days of rapamycin treatment, to characterize the early, intermediate, and late changes. Rapamycin significantly reduced CD4+ T cells, CD8+ T cells, and regulatory T (Treg) cells in peripheral LNs, mesenteric LNs, and the spleen over time. Rapamycin induced early pro-inflammation transition to pro-tolerogenic status, by modulating the LN laminin α4:α5 expression ratios (La4:La5) through LN stromal cells laminin α5 expression and by adjusting Treg numbers and distribution. Additionally, rapamycin significantly altered gut microbiota composition and metabolic functions, shifting the Bacteroides to Firmicutes ratio and increasing amino acid bioavailability in the gut lumen. These effects were evident by 7 days and became most pronounced by 30 days in naïve mice, with notable changes as early as 3 days in allogeneic splenocyte-stimulated mice. These findings reveal a novel mechanism of rapamycin action through time-dependent modulation of LN architecture and gut microbiome, which orchestrates changes in immune cell trafficking, providing a new framework for understanding and optimizing immunosuppressive therapies.

2025-04-30 | GSE288851 | GEO

Single cell RNA sequencing of TSCM predominnant allogeneic anti-BCMA CAR-T cells

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Project description:The purpose of this study is to determine the highest safe dose of rapamycin when given with a fixed amount of grapefruit juice.

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