Melanin Nanoparticles Alleviates Thalamic Stroke Damage by Modulating Glial Activation and Neuroinflammation

Thalamic strokes represent a major cause of post-stroke cognitive impairment, characterized by glial activation and disrupted iron homeostasis. Microglia and astrocytes play pivotal roles in the inflammatory response, but the mechanisms connecting glial activation to ferroptotic cell death remain unclear. This study explores the neuroprotective effects of melanin nanoparticles (MMPP) in thalamic stroke, focusing on glial activation and neuronal ferroptosis. Using a photothrombotic stroke model, MMPP nanoparticles suppress microglial activation, which subsequently mitigates astrocytic reactivity. Transcriptomic analysis reveals that MMPP nanoparticles regulate the MKK4/JNK signaling pathway, linking glial activation to ferroptosis. Reactive astrocytes secrete lipocalin-2 (LCN2), which triggers ferroptosis in neurons through the 24p3 receptor, causing iron accumulation and ROS production. Additionally, MMPP restores key ferroptosis markers by upregulating GPX4 and downregulating PTGS2, interrupting the pathological cascade, preserving neuronal antioxidant defenses, and reducing ferroptotic cell death. These findings highlight MMPP's dual antioxidant and anti-inflammatory effects, particularly through modulation of the microglia-astrocyte-LCN2 axis. This study suggests that MMPP provides a promising therapeutic strategy to alleviate neuroinflammation and promote functional recovery following ischemic stroke. Overall design: Seven days following photothrombotic surgery and melanin nanozyme injection in C57/BL mice, the thalamus was harvested for RNA sequencing.

丘脑卒中是卒中后认知障碍的主要致病因素之一，其病理特征为胶质细胞激活与铁稳态紊乱。小胶质细胞与星形胶质细胞在炎症反应中发挥关键作用，但连接胶质细胞激活与铁死亡的具体机制仍不明确。本研究探讨了黑色素纳米颗粒（melanin nanoparticles, MMPP）在丘脑卒中中的神经保护作用，重点关注胶质细胞激活与神经元铁死亡过程。本研究采用光血栓卒中模型，发现MMPP可抑制小胶质细胞激活，进而减轻星形胶质细胞的反应性活化。转录组分析显示，MMPP可调控MKK4/JNK信号通路，从而串联胶质细胞激活与铁死亡过程。反应性星形胶质细胞会分泌脂质运载蛋白-2（lipocalin-2, LCN2），后者通过24p3受体触发神经元铁死亡，引发铁蓄积与活性氧（reactive oxygen species, ROS）生成。此外，MMPP可通过上调GPX4、下调PTGS2恢复关键铁死亡标志物，阻断病理级联反应，维持神经元抗氧化防御能力，并减少铁死亡性细胞死亡。上述研究结果揭示了MMPP兼具抗氧化与抗炎的双重作用，尤其是通过调控小胶质细胞-星形胶质细胞-LCN2轴实现该效应。本研究表明，MMPP可为缓解缺血性卒中后的神经炎症、促进功能恢复提供极具潜力的治疗策略。实验整体设计：对C57/BL小鼠实施光血栓手术并注射黑色素纳米酶后第7天，采集丘脑组织进行RNA测序（RNA sequencing）。