炎症小体抑制纳米寡核苷酸在健康与疾病的三维人类运动皮层和前额叶皮层类器官中具有神经保护作用，缓解太空引起的病理变化

微重力和太空环境与神经肌肉和认知能力的缺陷有关，推测其原因在于太空中加速的衰老和神经退行性变化。尽管具体机制仍在研究中，但太空飞行相关的神经系统病理学是航天员和太空旅游者的重要健康风险，也在积极探索对策。然而，这种太空引起的神经病理学也为快速筛选治疗神经退行性疾病的靶点和候选药物提供了机遇。本研究展示了在地球上进行的高通量靶点筛选、靶点验证及利用我们的纳米寡核苷酸平台缓解微重力引起的神经病理学的初步证据，利用43天的SpaceX CRS-29任务送往国际空间站的实验。首先，通过比较健康与疾病状态的三维前额叶皮层（PFC，认知功能）和运动神经元（MN，神经肌肉功能）类器官，评估太空诱导的病理变化，检测与阿尔茨海默病（AD）、额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）相关的生物标志物。发现空间中健康和疾病类器官的神经退行性变化显著增强。其次，测试两种领先候选分子NI112（靶向NF-κB）和NI113（靶向IL-6），发现它们能显著减轻与AD、FTD和ALS相关的生物标志物如淀粉样β-42（Aβ42）、磷酸化Tau（pTau）、Kallikrein（KLK-6）、TDP-43等。此外，43天的纳米寡核苷酸治疗未在目标类器官中引起任何可观察到的毒性或安全性问题，显示出良好的耐受性。总体而言，这些结果显示了NI112和NI113作为潜在神经保护性对策在太空旅行中的发展和转化潜力，并证明太空环境在快速高通量筛选靶点和候选药物以实现临床转化方面的有用性。我们认为，微重力在药物开发和筛选中的应用，最终可能惠及数百万地球上患有严重神经退行性疾病的患者。

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.