siRNA nanoparticles targeting CaMKIIγ in lesional macrophages improve atherosclerotic plaque stability in mice

• Published in: Science translational medicine Vol. 12; no. 553
• Main Authors: Tao, Wei, Yurdagul, Jr, Arif, Kong, Na, Li, Wenliang, Wang, Xiaobo, Doran, Amanda C, Feng, Chan, Wang, Junqing, Islam, Mohammad Ariful, Farokhzad, Omid C, Tabas, Ira, Shi, Jinjun
• Format: Journal Article
• Language: English
• Published: United States 22.07.2020
• ISSN: 1946-6242
• DOI: 10.1126/SCITRANSLMED.AAY1063

Atherosclerotic lesional macrophages express molecules that promote plaque progression, but lack of mechanisms to therapeutically target these molecules represents a major gap in translational cardiovascular research. Here, we tested the efficacy of a small interfering RNA (siRNA) nanoparticle (NP) platform targeting a plaque-destabilizing macrophage molecule-Ca /calmodulin-dependent protein kinase γ (CaMKIIγ). CaMKIIγ becomes activated in advanced human and mouse plaque macrophages and drives plaque necrosis by suppressing the expression of the efferocytosis receptor MerTK. When macrophage-targeted siCamk2g NPs were administered to Western diet-fed mice, the atherosclerotic lesions showed decreased CaMKIIγ and increased MerTK expression in macrophages, improved phagocytosis of apoptotic cells (efferocytosis), decreased necrotic core area, and increased fibrous cap thickness-all signs of increased plaque stability-compared with mice treated with control siRNA NPs. These findings demonstrate that atherosclerosis-promoting genes in plaque macrophages can be targeted with siRNA NPs in a preclinical model of advanced atherosclerosis.