微重力和太空环境与神经肌肉和认知能力的缺陷有关，推测这是由于太空中加速衰老和神经退行性变所致。虽然具体机制仍在研究中，但与航天相关的神经病理学对宇航员和太空游客来说是一个重要的健康风险，目前正在积极研究以制定适当的对策。然而，这种太空诱发的神经病理学为加速筛选治疗神经退行性疾病的治疗靶点和先导分子提供了机会。在这里，我们展示了在为期 43 天的 SpaceX CRS-29 国际空间站任务中，使用我们的纳米低聚物平台进行的概念验证高通量目标筛选（在地球上）、目标验证和缓解微重力引起的神经病理学。首先，比较 3D 健康和患病的前额皮质（PFC，用于认知）和运动神经元（MN，用于神经肌肉功能）类器官，我们使用与阿尔茨海默病 (AD)、额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症（ALS）。通过相关疾病生物标志物测量，与各自的地球对照相比，健康和患病的 PFC 和 MN 类器官在太空中的神经变性均显着增强。其次，我们测试了前两个先导分子，即靶向 NF-κB 的 NI112 和靶向 IL-6 的 NI113。我们观察到这些纳米寡聚物显着减轻 AD、FTD 和 ALS 相关生物标志物，如淀粉样蛋白 β-42 (Aβ42)、磷酸化 tau (pTau)、激肽释放酶 (KLK-6)、Tar DNA 结合蛋白 43 (TDP-43)、和其他人。此外，对这些脑类器官进行 43 天的纳米低聚物治疗似乎并未在目标类器官组织中引起任何可观察到的毒性或安全问题，这表明这些分子在生理相关剂量下在大脑中具有良好的耐受性。总之，这些结果显示了 NI112 和 NI113 分子的开发和翻译作为更安全太空旅行的潜在神经保护对策的巨大潜力，并证明了太空环境对于快速、高通量筛选用于临床翻译的靶标和先导分子的有用性。我们断言，在药物开发和筛选中使用微重力可能最终使地球上数百万患有神经退行性疾病的患者受益。

The microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.