Department of Neurosurgery, Renmin Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430060, China.
J Med Chem. 2024 Jul 25;67(14):12428-12438. doi: 10.1021/acs.jmedchem.4c01208. Epub 2024 Jul 12.
Targeting Ca/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages using RNAi nanotechnology represents an innovative and promising strategy in the diagnosis and treatment of atherosclerosis. Nevertheless, it remains elusive because of the current challenges associated with the systemic delivery of siRNA nanoparticle (NP) to atheromatous plaques and the complexity of atherosclerotic plaques. Here, we demonstrate the potential of a thienothiadiazole-based near-infrared-II (NIR-II) organic aggregation-induced emission (AIE) platform encapsulated with the Camk2g siRNA to effectively target CaMKIIγ in macrophages for dynamic imaging and image-guided gene therapy of atherosclerosis. The nanoparticles effectively decreased CaMKIIγ expression and increased the expression of the efferocytosis receptor MerTK in plaque macrophages, leading to a reduction in the necrotic core area of the lesion in an aortic plaque model. Our theranostic approach highlights the substantial promise of near-infrared II (NIR-II) AIEgens for imaging and image-guided therapy of atherosclerosis.
利用 RNAi 纳米技术靶向巨噬细胞中的 Ca/calmodulin 依赖性蛋白激酶 γ (CaMKIIγ) 是一种创新且有前途的动脉粥样硬化诊断和治疗策略。然而，由于目前将 siRNA 纳米颗粒 (NP) 系统递送至动脉粥样硬化斑块以及斑块复杂性相关的挑战，该策略仍难以实现。在这里，我们展示了基于噻吩并[3,2-d]噻二唑的近红外-II (NIR-II) 有机聚集诱导发射 (AIE) 平台的潜力，该平台封装了 Camk2g siRNA，可有效靶向巨噬细胞中的 CaMKIIγ，用于动脉粥样硬化的动态成像和图像引导基因治疗。纳米颗粒有效降低了斑块巨噬细胞中 CaMKIIγ 的表达，并增加了吞噬作用受体 MerTK 的表达，从而减少了主动脉斑块模型中病变的坏死核心面积。我们的治疗方法突显了近红外-II (NIR-II) AIEgens 用于动脉粥样硬化成像和图像引导治疗的巨大潜力。
