Cheng Qian, Zhang Yufei, Su Guomin, Xue Yuhao, Zou Xinyu, Syeda Madiha Zahra, Jie Ruwei, Wan Jinlong, Li Yang, Bi Qiuchen, Zhu Heping, Bai He, Nirala Sanjeev, Lan Qing, Tang Longguang, Mu Qingchun
Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Basic Medical College, Guilin Medical University, Guilin, 541199, China.
Basic Medical College, Guilin Medical University, Guilin, 541199, China.
Acta Biomater. 2025 Sep 12. doi: 10.1016/j.actbio.2025.09.015.
Ischemic stroke remains a critical global health challenge with limited therapeutic options targeting secondary neuroinflammation. Emerging evidence implicates neutrophil extracellular traps (NETs) as key mediators of blood-brain barrier (BBB) disruption and neuronal damage during ischemia-reperfusion injury. Capitalizing on this pathophysiology, we engineered a neutrophil-homing lipid nanoparticle (LNP) platform encapsulating brensocatib (AZD7986), an FDA-designated breakthrough therapy that inhibits dipeptidyl peptidase 1 (DPP1) to block activation of neutrophil serine proteases. The LNPs exploit intrinsic neutrophil chemotaxis to achieve BBB penetration and lesion-specific accumulation, enabling localized release of AZD7986 in ischemic brain tissue. In a murine middle cerebral artery occlusion (MCAO) model, targeted LNP delivery (T-AZD) significantly prolonged survival, reduced cerebral infarct volume by 45 %, and suppressed NET formation through inhibition of elastase and cathepsin G activity (p < 0.01 vs. non-targeted controls). Mechanistically, T-AZD attenuated reactive astrogliosis and decreased pro-inflammatory cytokine levels (IL-6, TNF-α) by >50 %, demonstrating dual anti-inflammatory and neuroprotective effects. This neutrophil-directed nanoplatform addresses critical limitations of systemic DPP1 inhibition through spatiotemporal control of drug release, while exhibiting enhanced biocompatibility in hematological and histological safety assessments. By integrating targeted neutrophil trafficking with precision protease inhibition, our strategy establishes a translatable paradigm for modulating neuroimmune responses in cerebrovascular diseases. STATEMENT OF SIGNIFICANCE: Ischemic stroke lacks effective therapies targeting neuroinflammation. We developed neutrophil-homing lipid nanoparticles (LNPs) delivering brensocatib (AZD7986), a DPP1 inhibitor, to suppress neutrophil extracellular traps (NETs) and neuroinflammation. In a murine stroke model, targeted LNPs reduced infarct volume by 45 %, inhibited NET formation, and lowered pro-inflammatory cytokines (>50 %), demonstrating neuroprotection and anti-inflammatory effects. This approach enables precise drug delivery to ischemic brain tissue, overcoming limitations of systemic therapy while maintaining safety. By combining neutrophil-directed targeting with protease inhibition, our strategy offers a translatable platform for modulating neuroimmune responses in cerebrovascular diseases.
缺血性中风仍然是一项严峻的全球健康挑战，针对继发性神经炎症的治疗选择有限。新出现的证据表明，中性粒细胞胞外诱捕网（NETs）是缺血再灌注损伤期间血脑屏障（BBB）破坏和神经元损伤的关键介质。基于这种病理生理学，我们设计了一种归巢于中性粒细胞的脂质纳米颗粒（LNP）平台，该平台包裹了布瑞索替（AZD7986），这是一种美国食品药品监督管理局指定的突破性疗法，可抑制二肽基肽酶1（DPP1）以阻断中性粒细胞丝氨酸蛋白酶的激活。这些LNP利用中性粒细胞固有的趋化性实现血脑屏障穿透和病变特异性蓄积，从而使AZD7986在缺血性脑组织中局部释放。在小鼠大脑中动脉闭塞（MCAO）模型中，靶向LNP递送（T-AZD）显著延长了生存期，使脑梗死体积减少了45%，并通过抑制弹性蛋白酶和组织蛋白酶G的活性抑制了NET的形成（与非靶向对照相比，p<0.01）。从机制上讲，T-AZD减轻了反应性星形胶质细胞增生，并使促炎细胞因子水平（IL-6、TNF-α）降低了50%以上，显示出双重抗炎和神经保护作用。这种针对中性粒细胞的纳米平台通过对药物释放的时空控制解决了全身性DPP1抑制的关键局限性，同时在血液学和组织学安全性评估中表现出增强的生物相容性。通过将靶向中性粒细胞运输与精确的蛋白酶抑制相结合，我们的策略建立了一种可转化的范式，用于调节脑血管疾病中的神经免疫反应。
缺血性中风缺乏针对神经炎症的有效疗法。我们开发了递送DPP1抑制剂布瑞索替（AZD7986）的归巢于中性粒细胞的脂质纳米颗粒（LNP），以抑制中性粒细胞胞外诱捕网（NETs）和神经炎症。在小鼠中风模型中，靶向LNP使梗死体积减少了45%，抑制了NET的形成，并降低了促炎细胞因子水平（>50%），显示出神经保护和抗炎作用。这种方法能够将药物精确递送至缺血性脑组织，克服了全身治疗的局限性，同时保持了安全性。通过将针对中性粒细胞的靶向与蛋白酶抑制相结合，我们的策略为调节脑血管疾病中的神经免疫反应提供了一个可转化的平台。
