Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
Leon H. Charney Division of Cardiology, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016, United States.
ACS Nano. 2023 Sep 26;17(18):17721-17739. doi: 10.1021/acsnano.3c00958. Epub 2023 Sep 5.
Atherosclerosis is a common pathology present in many cardiovascular diseases. Although the current therapies (including statins and inhibitors of the serine protease PCSK9) can effectively reduce low-density lipoprotein (LDL) cholesterol levels to guideline-recommended levels, major adverse cardiovascular events still occur frequently. Indeed, the subendothelial retention of lipoproteins in the artery wall triggers multiple events of inflammation in macrophages and is a major contributor to the pathological progression of atherosclerosis. It has been gradually recognized that modulating inflammation is, therefore, an attractive avenue to forestall and treat atherosclerosis and its complications. Unfortunately, challenges with specificity and efficacy in managing plaque inflammation have hindered progress in atherosclerosis treatment. Herein, we report an NP-mediated mRNA therapeutic approach to target atherosclerotic lesional macrophages, modulating inflammation in advanced atherosclerotic lesions for the treatment of atherosclerosis. We demonstrated that the targeted NPs containing mRNA colocalized with M2-like macrophages and induced IL-10 production in atherosclerotic plaques following intravenous administration to Western diet (WD)-fed mice. Additionally, the lesions showed a significantly alleviated inflammatory response, as evidenced by reduced oxidative stress and macrophage apoptosis, resulting in decreased lipid deposition, diminished necrotic areas, and increased fiber cap thickness. These results demonstrate the successful delivery of mRNA therapeutics to macrophage-enriched plaques in a preclinical model of advanced atherosclerosis, showing that this targeted NP inflammation management approach has great potential for translation into a wide range of clinical applications.
动脉粥样硬化是许多心血管疾病中常见的病理学表现。尽管目前的治疗方法（包括他汀类药物和丝氨酸蛋白酶 PCSK9 抑制剂）可以有效地将低密度脂蛋白（LDL）胆固醇水平降低到指南推荐的水平，但主要不良心血管事件仍频繁发生。事实上，脂蛋白在动脉壁中的内皮下滞留会引发巨噬细胞中的多种炎症事件，是动脉粥样硬化病理进展的主要原因。人们逐渐认识到，调节炎症是预防和治疗动脉粥样硬化及其并发症的一种有吸引力的方法。不幸的是，在管理斑块炎症的特异性和疗效方面存在挑战，阻碍了动脉粥样硬化治疗的进展。在此，我们报告了一种 NP 介导的 mRNA 治疗方法，用于靶向动脉粥样硬化病变中的巨噬细胞，调节晚期动脉粥样硬化病变中的炎症，从而治疗动脉粥样硬化。我们证明，含有 mRNA 的靶向 NPs 与 Western 饮食（WD）喂养的 小鼠的动脉粥样硬化斑块中的 M2 样巨噬细胞共定位，并在静脉注射后诱导 IL-10 产生。此外，病变显示出炎症反应明显减轻，这表现为氧化应激和巨噬细胞凋亡减少，导致脂质沉积减少、坏死区减少和纤维帽厚度增加。这些结果证明了 mRNA 治疗药物在晚期动脉粥样硬化的临床前模型中成功递送到富含巨噬细胞的斑块，表明这种靶向 NP 炎症管理方法具有广泛应用于多种临床应用的巨大潜力。
