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Nanoparticle-boosted myeloid-derived suppressor cell therapy for immune reprogramming in multiple sclerosis

ABSTRACT: Massive immune cell infiltration and persistent inflammation in the central nervous system (CNS) are key hallmarks of multiple sclerosis, an incurable autoimmune disease. Here, we report a myeloid-derived suppressor cell (MDSC)-based therapeutic strategy, named CNS Immune Targeting Enabled by MDSCs (CITED), which employs surface-decorated MDSCs carrying rapamycin nanoparticles (NPs) for targeted multimodal immune reprograming in the CNS. We show that NP decoration enhances MDSC immunomodulatory function, facilitates their trafficking to inflamed CNS regions, and increases NP accumulation within the CNS. In an experimental autoimmune encephalomyelitis (EAE) model, CITED exhibited robust therapeutic efficacy, resulting in reduced disease progression, improved motor function, and diminished myelin damage. Mechanistic studies reveal that CITED exerts its therapeutic effects by targeted reprogramming both innate and adaptive immune responses in CNS. Specifically, CITED inhibits immune cell infiltration, rebalances CD4 T cell phenotypes, and promotes the polarization of myeloid cells toward anti-inflammatory phenotypes. Collectively, CITED could provide a broadly effective approach for targeted immune restoration in multiple sclerosis and potentially other autoimmune diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE306006 | GEO | 2025/08/25

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that accumulate in the tumor microenvironment of most cancer patients. There MDSCs suppress both adaptive and innate immune responses, hindering immunotherapies. Moreover, many cancers are accompanied by inflammation, a processes that further intensifies MDSC suppressive activity, causing aggressive tumor progression and metastasis. MDSCs collected from tumor-bearing mice profusely release nano-scale membrane-bound extracellular vesicles, called exosomes, which carry biologically active proteins between cells and contribute directly to the immune suppressive functions of MDSC. Many studies on other cell types have shown that exosomes may also carry microRNAs (miRNAs) and messenger RNAs (mRNAs) which can also be transferred to surrounding and distant cells. However, to the best of our knowledge, the miRNA and mRNA cargo of MDSC-derived exosomes has not yet been interrogated. This study aims to identify and quantify the cargo of MDSC and their immunosuppressive exosomes to gather knowledge that can offer insights on the mechanisms by which MDSCs contribute to immune suppression, focusing on the role of exosomes as intercellular communication mediators in the tumor microenvironment. In order to achieve our objective a well-established mouse model based on a conventional mammary carcinoma (4T1 cells) and heightened inflammation (4T1 transduced to express the cytokine interleukin-1b) was used. We provide evidence that MDSC-derived exosomes carry proteins, mRNAs and miRNAs. Relative quantitation demonstrated quantitative differences between the exosome cargo and the cargo of their parental cells, supporting the hypothesis that selective loading into the exosomes is possible. Additionally, quantitative and functional analyses of the exosome cargo generated under conventional and heightened inflammation conditions are consistent with clinical observations that inflammation is linked to cancer development.

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Nanoparticle-boosted myeloid-derived suppressor cell therapy for immune reprogramming in multiple sclerosis

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