{
  "abstract": "Background: Parkinson's disease (PD) is characterized by the progressive loss of midbrain dopaminergic (DA) neurons and aberrant alpha-synuclein (alpha-syn) aggregation, yet disease-modifying therapies that simultaneously retard neurodegeneration and foster regeneration remain lacking. Methods: In this study, we isolated extracellular vesicles (TH and FOXA2 double-positive cell-derived EVs) from TH and FOXA2 double-positive differentiated neural cells, a distinct midbrain floor-plate-derived neural cell population that co-expresses the floor-plate transcription factor FOXA2 together with TH and should therefore not be equated with conventional mature midbrain dopaminergic neurons, and systematically evaluated their therapeutic potential across three complementary models: A53T transgenic mice, 6-OHDA-lesioned rats, and 6-OHDA-treated human midbrain organoids. Integrative transcriptomic and single-cell sequencing analyses, together with toxicological evaluations in rodents and non-human primates, were performed to investigate the underlying mechanisms and safety profile. These TH and FOXA2 double-positive cells were generated using a fully suspension-based, matrix-free, and chemically defined differentiation system devoid of N2/B27 supplements and fetal bovine serum (FBS). This approach offers a simple, controllable, low-cost, and scalable platform with high batch-to-batch consistency for EV manufacturing. Throughout this study, the term \"TH and FOXA2 double-positive cells\" refers to this distinct TH and FOXA2 double-positive cell population and should not be interpreted as conventional terminally differentiated dopaminergic neurons. Results: Intranasal administration of TH and FOXA2 double-positive cell-derived EVs in A53T mice and 6-OHDA-lesioned rats significantly ameliorated motor deficits, increased nigral tyrosine hydroxylase (TH)-positive neuron counts, reduced alpha-syn aggregation, and suppressed gliosis. In human midbrain organoids, TH and FOXA2 double-positive cell-derived EVs preserved DA neuronal morphology and reduced GFAP and alpha-syn expression. Notably, when EVs were administered simultaneously with 6-OHDA modeling rather than after modeling was completed, the protective effect was stronger. Multi-omics analysis revealed that TH and FOXA2 double-positive cell-derived EVs reversed pathological signatures of interferon-responsive microglia and oxidative stress-adapted astrocytes, while restoring WNT- and non-canonical WNT-mediated intercellular communications. Safety evaluations showed no discernible organ toxicity. Conclusions: TH and FOXA2 double-positive cell-derived EVs exert neuroprotective effects across multiple PD models by modulating specific glial subpopulations and reinstating development-associated signaling pathways. Together with a fully suspension-based, matrix-free, and N2/B27-free differentiation process that enables low-cost, scalable, and highly reproducible manufacturing, TH and FOXA2 double-positive cell-derived EVs represent a promising therapeutic candidate for Parkinson's disease.",
  "abstract_shown": true,
  "affiliations": [
    "Putuo Hospital, Shanghai University of Traditional Chinese Medicine"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Z. Liu"
    },
    {
      "name": "Z. Qi"
    },
    {
      "name": "X. Li"
    },
    {
      "name": "X. Jin"
    },
    {
      "name": "C. Shen"
    },
    {
      "name": "L. Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Y. Liu"
    },
    {
      "name": "M. Huang"
    },
    {
      "name": "L. Xing"
    },
    {
      "name": "Y. Chen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b8xtxfww6hbhk.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.22.753408",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753408v1.full",
  "id": "b8xtxfww6hbhk",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753408v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "1312|Extracellular vesicles in disease"
    ]
  ],
  "openalex": "W7214663893",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753408v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/b8xtxfww6hbhk.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:54Z",
      "native_id": "10.64898/2026.09.22.753408",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753408v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Therapeutic Potential of iPSC-Derived TH+FOXA2+ Neuronal Extracellular Vesicles in Parkinson's Disease Revealed by Organoid and Rodent Models",
  "title_text": "Therapeutic Potential of iPSC-Derived TH+FOXA2+ Neuronal Extracellular Vesicles in Parkinson's Disease Revealed by Organoid and Rodent Models",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:27Z",
  "url": "https://research.draconitic.com/paper/b8xtxfww6hbhk",
  "venue": "bioRxiv",
  "versions": []
}