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Background <p>Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes.</p> Results <p>In this study, we demonstrate that PpSEVs efficiently penetrate the blood-brain barrier and show relative enrichment in the hippocampus CA3 region of 5×FAD mice. Transcriptomic profiling and functional assays reveal that PpSEVs reverse AD pathology by reconfiguring the dysregulated neuroimmune network rather than through broad immune suppression. Specifically, PpSEVs exert a dual-action effect on microglia by blocking caspase-1/GSDMD axis-mediated pyroptosis, while simultaneously enhancing CD68-dependent amyloid-β clearance. This microglial modulation occurs in tandem with the reprogramming of reactive astrocytes, characterized by the downregulation of neurotoxic C3 and the upregulation of neuroprotective S100A10. Furthermore, we identify a direct, glia-independent neurotrophic pathway in which PpSEVs activate neuronal BDNF signaling to rescue synaptic integrity and cognitive function.</p> Conclusions <p>By demonstrating robust cross-species efficacy without provoking immunotoxicity, our study positions PpSEVs as a potent, multi-target intervention that decouples therapeutic benefits from human donor reliance, paving the way for sustainable, xenogeneic exosome-based AD therapies.</p>

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Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer’s disease pathology in a 5×FAD mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Xiaoyang Lu,
  • Yiling Jiang,
  • Xiuqing Lin,
  • Yuanxing Zhang,
  • Qin Liu,
  • Shouwen Chen

摘要

Background

Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes.

Results

In this study, we demonstrate that PpSEVs efficiently penetrate the blood-brain barrier and show relative enrichment in the hippocampus CA3 region of 5×FAD mice. Transcriptomic profiling and functional assays reveal that PpSEVs reverse AD pathology by reconfiguring the dysregulated neuroimmune network rather than through broad immune suppression. Specifically, PpSEVs exert a dual-action effect on microglia by blocking caspase-1/GSDMD axis-mediated pyroptosis, while simultaneously enhancing CD68-dependent amyloid-β clearance. This microglial modulation occurs in tandem with the reprogramming of reactive astrocytes, characterized by the downregulation of neurotoxic C3 and the upregulation of neuroprotective S100A10. Furthermore, we identify a direct, glia-independent neurotrophic pathway in which PpSEVs activate neuronal BDNF signaling to rescue synaptic integrity and cognitive function.

Conclusions

By demonstrating robust cross-species efficacy without provoking immunotoxicity, our study positions PpSEVs as a potent, multi-target intervention that decouples therapeutic benefits from human donor reliance, paving the way for sustainable, xenogeneic exosome-based AD therapies.