Wu Yina, Park Jinwon, Le Quoc-Viet, Byun Junho, Choi Jaehyun, Xu Enzhen, Lee Jaiwoo, Oh Yu-Kyoung
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam.
Nat Commun. 2024 Dec 30;15(1):10747. doi: 10.1038/s41467-024-54817-7.
Delivering protein drugs to the central nervous system (CNS) is challenging due to the blood-brain and blood-spinal cord barrier. Here we show that neutrophils, which naturally migrate through these barriers to inflamed CNS sites and release neutrophil extracellular traps (NETs), can be leveraged for therapeutic delivery. Tannic acid nanoparticles tethered with anti-Ly6G antibody and interferon-β (aLy6G-IFNβ@TLP) are constructed for targeted neutrophil delivery. These nanoparticles protect interferon-β from reactive oxygen species and preferentially accumulate in neutrophils over other immune cells. Upon encountering inflammation, neutrophils release the nanoparticles during NET formation. In the female mouse model of experimental autoimmune encephalomyelitis, intravenous administration of aLy6G-IFNβ@TLP reduce disease progression and restore motor function. Although this study focuses on IFNβ and autoimmune encephalomyelitis, the concept of hitchhiking neutrophils for CNS delivery and employing NET formation for inflamed site-specific nanoparticle release can be further applied for delivery of other protein drugs in the treatment of neurodegenerative diseases.
由于血脑屏障和血脊髓屏障，将蛋白质药物递送至中枢神经系统（CNS）具有挑战性。在此我们表明，中性粒细胞可用于治疗性递送，中性粒细胞能自然迁移通过这些屏障到达炎症性中枢神经系统部位并释放中性粒细胞胞外诱捕网（NETs）。构建了与抗Ly6G抗体和干扰素-β 拴系的单宁酸纳米颗粒（aLy6G-IFNβ@TLP）用于靶向递送中性粒细胞。这些纳米颗粒保护干扰素-β 免受活性氧的影响，并且相较于其他免疫细胞，优先在中性粒细胞中积累。遇到炎症时，中性粒细胞在形成NETs的过程中释放纳米颗粒。在实验性自身免疫性脑脊髓炎的雌性小鼠模型中，静脉注射aLy6G-IFNβ@TLP可减缓疾病进展并恢复运动功能。尽管本研究聚焦于干扰素-β 和自身免疫性脑脊髓炎，但搭乘中性粒细胞进行中枢神经系统递送以及利用NETs形成实现炎症部位特异性纳米颗粒释放的概念，可进一步应用于递送其他蛋白质药物以治疗神经退行性疾病。
