Han Ranran, Lan Xi, Han Zheng, Ren Honglei, Aafreen Safiya, Wang Wenshen, Hou Zhipeng, Zhu Tianyue, Qian Andrew, Han Xiaoning, Koehler Raymond C, Liu Guanshu
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, MD, USA; Center for Health Systems Innovation, Oklahoma State University, Stillwater, OK, 74078, USA.
Biomaterials. 2023 Oct;301:122277. doi: 10.1016/j.biomaterials.2023.122277. Epub 2023 Aug 15.
Intracerebral hemorrhage (ICH) remains the most lethal type of stroke, and effective clinical therapies that can speed up hematoma resolution after ICH are still lacking. While the beneficial effects of IL-10 on ICH recovery have been demonstrated, the clinical translation of IL-10 requires effective delivery methods by which sufficient IL-10 can be delivered to ICH-affected regions in the brain. Here we report the use of a phosphatidylserine (PS) liposome (PSL)-based nanoparticle system for microglia/macrophage-targeted delivery of IL-10 in ICH. We first prepared IL-10-conjugated PSL (PSL-IL10) and characterized their immunomodulating effects in vitro. Then we evaluated the therapeutic effects, including hematoma absorption, short-term outcomes, and neuroinflammation, of intranasally administered PSL-IL10 (3 μg IL-10 per mouse, 2 h post-ICH) in a collagenase-induced ICH mouse model. We also isolated microglia/macrophages from the mouse brains with ICH to analyze their morphology, phagocytosis ability, and polarization. Our study reveals that, 1) PSL-IL10 treatment resulted in significantly improved outcomes and accelerated hematoma resolution in the acute phase of ICH; 2) PSL-IL10 inhibited glial activation and down-regulated pro-inflammatory cytokine production; 3) PSL-IL10 induced Iba1 cells with a stronger phagocytosis ability; 4) PSL-IL10 activated STAT3 and upregulated CD36 expression in microglia/macrophage. These findings collectively show that PSL-IL10 is a promising nanotherapeutic for effectively ameliorating ICH.
脑出血（ICH）仍然是最致命的中风类型，目前仍缺乏能够加速脑出血后血肿吸收的有效临床治疗方法。虽然白细胞介素-10（IL-10）对脑出血恢复的有益作用已得到证实，但IL-10的临床应用需要有效的给药方法，以便将足够的IL-10输送到大脑中受脑出血影响的区域。在此，我们报告了一种基于磷脂酰丝氨酸（PS）脂质体（PSL）的纳米颗粒系统，用于在脑出血中向小胶质细胞/巨噬细胞靶向递送IL-10。我们首先制备了IL-10偶联的PSL（PSL-IL10），并在体外对其免疫调节作用进行了表征。然后，我们在胶原酶诱导的脑出血小鼠模型中评估了经鼻给药的PSL-IL10（每只小鼠3μg IL-10，脑出血后2小时）的治疗效果，包括血肿吸收、短期预后和神经炎症。我们还从小鼠脑出血模型的大脑中分离出小胶质细胞/巨噬细胞，以分析它们的形态、吞噬能力和极化情况。我们的研究表明，1）PSL-IL10治疗可显著改善脑出血急性期的预后并加速血肿吸收；2）PSL-IL10抑制胶质细胞活化并下调促炎细胞因子的产生；3）PSL-IL10诱导具有更强吞噬能力的Iba1细胞；4）PSL-IL10激活STAT3并上调小胶质细胞/巨噬细胞中CD36的表达。这些发现共同表明，PSL-IL10是一种有望有效改善脑出血的纳米治疗药物。
