抑制炎症体的纳米脂质体对健康和患病的三维人运动和前额叶皮层脑器官的空间诱导的病理具有神经保护作用

微重力和空间环境与神经肌肉和认知能力的缺陷有关，该缺陷由于空间中的衰老和神经变性而导致发生。尽管仍在研究具体机制，但与太空飞行相关的神经病理学对宇航员和太空游客来说是重要的健康风险，并且正在积极调查适当的对策。但是，这种空间引起的神经病理学为筛查治疗神经退行性疾病的治疗靶标和铅分子提供了机会。在这里，我们使用我们的纳米聚合物平台（On Nonoligomer平台）在43天SpaceX CRS-29任务上向国际空间站展示了概念验证的高通量目标筛查（在地球上），目标验证以及微重力诱导的神经病理学的缓解。首先，比较3D健康和患病的前额叶皮层（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氏病（AD），额叶痴呆症（FTD）和Amyytroploploploplossclor的生物标志物评估了空间诱导的病理学。与各自的地球对照相比，通过相关疾病生物标志物测量的健康和患病的PFC和MN器官在空间中均显示出显着增强的神经退行性。其次，我们测试了针对靶向IL-6的NF-κB和NI113的前两个铅分子Ni112。我们观察到，这些纳米素体可显着减轻AD，FTD和ALS相关的生物标志物，例如淀粉样蛋白β-42（Aβ42），磷酸化TAU（PTAU），Kallikrein（Kallikrein（KLK-6），TAR DNA结合蛋白43（TDP-43）（TDP-43），以及其他。此外，这些脑器官的43天纳米聚物治疗似乎并未引起靶心器官组织中任何可观察到的毒性或安全性问题，这表明在生理上相关剂量时，这些分子在大脑中良好的耐受性。总之，这些结果表明了Ni112和Ni113分子的发展和翻译的显着潜力，这是对更安全的空间旅行的潜在神经保护对策，并证明了空间环境对靶标的快速，高通量筛查的有用性，以及用于临床翻译的铅分子。我们断言，在药物开发和筛查中使用微重力可能会使数百万患有地球上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.