Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, China.
Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, China.
Theranostics. 2024 Jan 1;14(1):283-303. doi: 10.7150/thno.90370. eCollection 2024.
Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease resulting from blood extravasating into the brain parenchyma. Escalation of erythrophagocytosis (a form of efferocytosis), avoiding the consequent release of the detrimental erythrocyte lysates, may be a promising target of ICH management. The ADAM17 inhibitor and liver X receptor (LXR) agonist could promote efficient efferocytosis and injury repair. Nevertheless, the poor bioavailability and restriction of the blood-brain barrier (BBB) hinder their application. Therefore, it is needed that biocompatible and smart nanoplatforms were designed and synthesized to realize effective therapy targeting erythrophagocytosis. We first assessed the synergistic effect of therapeutic GW280264X (an ADAM17 inhibitor) and desmosterol (an LXR agonist) on erythrophagocytosis . Then a pH-responsive neutrophil membrane-based nanoplatform (NPEOz) served as a carrier to accurately deliver therapeutic GW280264X and desmosterol to the damaged brain was prepared via co-extrusion. Afterwards, their pH-responsive performance was valued and targeting ability was assessed through fluorescence image Finally, the pro-erythrophagocytic and anti-neuroinflammatory ability of the nanomedicine and related mechanisms were investigated. After the synergistical effect of the above two drugs on erythrophagocytosis was confirmed, we successfully developed neutrophil-disguised pH-responsive nanoparticles to efficiently co-deliver them. The nanoparticles could responsively release therapeutic agents under acidic environments, and elicit favorable biocompatibility and ability of targeting injury sites. D&G@NPEOz nanoparticles enhanced erythrophagocytosis through inhibiting shedding of the efferocytotic receptors MERTK/AXL mediated by ADAM17 and accelerating ABCA-1/ABCG-1-mediated cholesterol efflux regulated by LXR respectively. In addition, the nano-formulation was able to modulate the inflammatory microenvironment by transforming efferocytes towards a therapeutic phenotype with reducing the release of proinflammatory cytokines while increasing the secretion of anti-inflammatory factors, and improve neurological function. This biomimetic nanomedicine is envisaged to offer an encouraging strategy to effectively promote hematoma and inflammation resolution, consequently alleviate ICH progression.
脑出血（ICH）是一种破坏性的脑血管疾病，其特征是血液渗出到脑实质中。促进红细胞吞噬作用（一种吞噬作用形式），避免红细胞裂解物的有害释放，可能是 ICH 治疗的一个有前途的靶点。ADAM17 抑制剂和肝 X 受体（LXR）激动剂可以促进有效的吞噬作用和损伤修复。然而，较差的生物利用度和血脑屏障（BBB）的限制阻碍了它们的应用。因此，需要设计和合成生物相容性和智能纳米平台，以实现针对红细胞吞噬作用的有效治疗。
我们首先评估了治疗性 GW280264X（ADAM17 抑制剂）和去甲胆固醇（LXR 激动剂）对红细胞吞噬作用的协同作用。然后，通过共挤出法制备了一种 pH 响应性中性粒细胞膜基纳米平台（NPEOz），作为载体将治疗性 GW280264X 和去甲胆固醇准确递送到受损的大脑。随后，评估了它们的 pH 响应性能，并通过荧光图像评估了它们的靶向能力。最后，研究了纳米药物的促红细胞吞噬作用和抗神经炎症能力及其相关机制。
在确认上述两种药物对红细胞吞噬作用的协同作用后，我们成功开发了中性粒细胞伪装的 pH 响应性纳米粒子来有效地共递送它们。纳米粒子可以在酸性环境下响应性地释放治疗剂，并表现出良好的生物相容性和靶向损伤部位的能力。D&G@NPEOz 纳米粒子通过抑制 ADAM17 介导的吞噬作用受体 MERTK/AXL 的脱落和加速 LXR 调节的 ABCA-1/ABCG-1 介导的胆固醇外排，增强了红细胞吞噬作用。此外，该纳米制剂还可以通过将吞噬细胞转化为具有治疗表型来调节炎症微环境，减少促炎细胞因子的释放，增加抗炎因子的分泌，从而改善神经功能。
这种仿生纳米药物有望提供一种有希望的策略，有效地促进血肿和炎症的消退，从而减轻 ICH 的进展。
