Kaur Chanpreet, Villarreal Ellaina, Cabe Maleen H, Langert Kelly A
Department of Molecular Pharmacology and Neuroscience, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Avenue, Bldg 115, Room 416, Maywood, IL, 60153, USA.
Research Service, Edward Hines Jr. VA Hospital, Hines, IL, 60141, USA.
Sci Rep. 2025 Apr 6;15(1):11763. doi: 10.1038/s41598-025-96231-z.
Guillain-Barré syndrome (GBS) is a devastating autoimmune disease of the peripheral nervous system (PNS) with limited treatment options. Several studies have shown attenuation of the well-characterized GBS preclinical experimental autoimmune neuritis (EAN) model with systemically administered therapeutic compounds via anti-inflammatory or immunomodulatory mechanisms. Despite this, clinical advancement of these findings is limited by dosing that is not translatable to humans or is associated with off-target and toxic effects. This is due, in part, to the blood-nerve barrier (BNB), which restricts access of the circulation to peripheral nerves. However, during acute neuroinflammation, the normally restrictive BNB exhibits increased vascular permeability and enables immune cell infiltration. This may offer a unique window to access the otherwise restricted peripheral nerve microenvironment for therapeutic delivery. Here, we assessed the degree to which BNB permeability and immune cell infiltration over the course of EAN enables accumulation of circulating nanoparticles. We found that at disease stages defined by distinct clinical scores and pathology (onset, effector phase, and peak of EAN severity), intravenously administered small molecules and nanoparticles ranging from 50 to 150 nm can permeate into the endoneurium from the endoneurial vasculature in a size- and stage-dependent manner. This permeation occurs uniformly in both sciatic nerves and in proximal and distal regions of the nerves. We propose that this nerve targeting enabled by pathology serves as a platform by which potential therapies for GBS can be reevaluated and investigated preclinically in nanoparticle delivery systems.
格林-巴利综合征（GBS）是一种破坏性的外周神经系统（PNS）自身免疫性疾病，治疗选择有限。多项研究表明，通过抗炎或免疫调节机制全身给药治疗性化合物，可使特征明确的GBS临床前实验性自身免疫性神经炎（EAN）模型病情减轻。尽管如此，这些研究结果在临床上的进展受到限制，原因是给药剂量无法转化为人体适用剂量，或者与脱靶效应和毒性作用相关。部分原因在于血-神经屏障（BNB），它限制了循环系统与外周神经的接触。然而，在急性神经炎症期间，通常具有限制性的BNB会表现出血管通透性增加，并使免疫细胞浸润。这可能为进入原本受限的外周神经微环境进行治疗性给药提供一个独特的窗口。在此，我们评估了在EAN病程中BNB通透性和免疫细胞浸润使循环纳米颗粒积累的程度。我们发现，在由不同临床评分和病理学定义的疾病阶段（EAN发病期、效应期和严重程度峰值），静脉注射的小分子和50至150纳米的纳米颗粒能够以大小和阶段依赖的方式从神经内膜血管渗透到神经内膜。这种渗透在坐骨神经以及神经的近端和远端区域均均匀发生。我们提出，这种由病理学实现的神经靶向作用可作为一个平台，通过该平台可在纳米颗粒递送系统中对GBS的潜在治疗方法进行重新评估和临床前研究。
