Zhang Tongyu, Liu Peixin, Shen Wenru, Li Chao, Zhao Zhenhao, Wu Yuxing, Sun Tao, Jiang Chen
Department of Pharmaceutics, School of Pharmaceutical Sciences, Fudan University, Shanghai, 201203, China.
Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Brain Function and Disorders, Shanghai, 201203, China.
Adv Sci (Weinh). 2025 Sep;12(34):e03689. doi: 10.1002/advs.202503689. Epub 2025 Jun 19.
The recruitment and formation of neutrophil extracellular traps (NETs) by neutrophils play an important role in reperfusion injury in ischemic stroke. Current nanosystem-based therapeutic strategies are mainly confined within the blood-brain barrier (BBB), ignoring the constant intrusion from external challenges. Here, considering the unique vascular localization of NETs, a DNase I-mediated NETs-targeting nanoparticle is developed to integrate the catalytic and chemotactic functions of DNase I and achieve the synergistic regulation of the internal and external microenvironment of the neurovascular unit (NVU). DNase I navigates the nanoparticles to the lesion, enabling the accumulation in the brain through damaged BBB. The removal of intravascular NETs mitigates the ongoing destruction of the endothelium and reduces the recruitment of immunothrombosis. The main nanoparticles with dual antioxidant activity rescue neuronal apoptosis by scavenging reactive oxygen species (ROS) and protecting mitochondria. Reduced infarct size and remodeling of microenvironment homeostasis shown in the middle cerebral artery occlusion/reperfusion (MCAO) mouse model. This strategy provides new insights into the vascular side treatment of ischemic stroke. Targeting mediated by enzyme chemotaxis is first validated and showed the potential of a universal chemotactic targeted delivery strategy.
中性粒细胞募集并形成中性粒细胞胞外陷阱（NETs）在缺血性脑卒中的再灌注损伤中起重要作用。当前基于纳米系统的治疗策略主要局限于血脑屏障（BBB）内，而忽略了外部挑战的持续侵扰。在此，考虑到NETs独特的血管定位，开发了一种脱氧核糖核酸酶I（DNase I）介导的靶向NETs的纳米颗粒，以整合DNase I的催化和趋化功能，并实现对神经血管单元（NVU）内外微环境的协同调节。DNase I引导纳米颗粒到达病变部位，使其能够通过受损的血脑屏障在脑内蓄积。清除血管内的NETs可减轻内皮细胞的持续破坏，并减少免疫血栓形成。具有双重抗氧化活性的主要纳米颗粒通过清除活性氧（ROS）和保护线粒体来挽救神经元凋亡。在大脑中动脉闭塞/再灌注（MCAO）小鼠模型中显示梗死体积减小，微环境稳态得以重塑。该策略为缺血性脑卒中的血管侧治疗提供了新的见解。首次验证了由酶趋化作用介导的靶向性，并显示了通用趋化靶向递送策略的潜力。
