Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China.
Department of Trauma-Emergency and Critical Care Medicine Center (TECCMC), Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
ACS Nano. 2024 Oct 15;18(41):28228-28245. doi: 10.1021/acsnano.4c08157. Epub 2024 Oct 5.
Sepsis-associated encephalopathy (SAE) is a devastating complication of sepsis, affecting approximately 70% of patients with sepsis in intensive care units (ICU). Although the pathophysiological mechanisms remain elusive, sepsis is typically accompanied by systemic inflammatory response syndrome (SIRS) and hyper-oxidative conditions. Here, we introduce a biomimetic nanomodulator (mAOI NP) that specifically targets inflammation site and simultaneously regulates oxidative and inflammatory stresses. mAOI NPs are constructed using metal-coordinated polyphenolic antioxidants (tannic acid) and flavonoid quercetin, which are then coated with macrophage membrane to enhance pharmacokinetics and enable SAE targeting. In a cecal ligation and puncture (CLP)-induced severe sepsis model, mAOI NPs effectively mitigate oxidative stress by purging reactive oxygen species, repairing mitochondrial damage and activating the Nrf2/HO-1 signaling pathway; while polarizing M1 macrophages or microglia toward anti-inflammatory M2 subtype. mAOI NPs potently inhibit sepsis progress, prolong overall survival from 25 to 66% and enhance learning and memory capabilities in SAE mice. Further proteomics analysis reveals that mAOI NPs modulate neurodevelopment processes related to learning and memory formation while also exerting anti-inflammatory and antioxidative effects on brain tissue responses associated with SAE pathology. This study offers significant potential for improving patient outcomes and revolutionizing the treatment landscape for this devastating complication of sepsis.
脓毒症相关性脑病（SAE）是脓毒症的一种严重并发症，影响约 70%的重症监护病房（ICU）脓毒症患者。尽管其病理生理机制尚不清楚，但脓毒症通常伴有全身炎症反应综合征（SIRS）和高氧化状态。在这里，我们介绍了一种仿生纳米调节剂（mAOI NP），它可以特异性地靶向炎症部位，同时调节氧化和炎症应激。mAOI NPs 由金属配位多酚抗氧化剂（单宁酸）和类黄酮槲皮素构建而成，然后用巨噬细胞膜包裹，以增强药代动力学并实现 SAE 靶向。在盲肠结扎穿孔（CLP）诱导的严重脓毒症模型中，mAOI NPs 通过清除活性氧、修复线粒体损伤和激活 Nrf2/HO-1 信号通路，有效减轻氧化应激；同时将 M1 巨噬细胞或小胶质细胞极化为抗炎的 M2 亚型。mAOI NPs 强力抑制脓毒症进展，将脓毒症小鼠的总存活率从 25%延长至 66%，并增强 SAE 小鼠的学习和记忆能力。进一步的蛋白质组学分析表明，mAOI NPs 调节与学习和记忆形成相关的神经发育过程，同时对与 SAE 病理相关的脑组织反应发挥抗炎和抗氧化作用。这项研究为改善患者预后和彻底改变脓毒症这一严重并发症的治疗前景提供了巨大的潜力。
