Pro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis

• Published in: Nature communications Vol. 15; no. 1; pp. 8034 - 13
• Main Authors: Bamezai, Sharika, Zhang, Yapei, Kumari, Manisha, Lotfi, Mozhgan, Alsaigh, Tom, Luo, Lingfeng, Kumar, Gayatri Suresh, Wang, Fudi, Ye, Jianqin, Puri, Madhu, Manchanda, Romila, Paluri, Sesha, Adkar, Shaunak S., Kojima, Yoko, Ingelsson, Alice, Bell, Caitlin F., Lopez, Nicolas G., Fu, Changhao, Choi, Ryan B., Miller, Zach, Barrios, Leo, Walsh, Susan, Ahmad, Ferhaan, Maegdefessel, Lars, Smith, Bryan Ronain, Leeper, Nicholas J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 13/51; 38/91; 59/78; 631/61/350/354; 692/308/2778; 692/699/75/593/2100; Accumulation; Anemia; Animal models; Animals; Apoptosis; Apoptosis - drug effects; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - pathology; Cardiovascular diseases; CD47 Antigen - antagonists & inhibitors; CD47 Antigen - metabolism; Disease Models, Animal; Erythrocytes; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Inflammation; Inflammation - pathology; Inflammatory diseases; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Phagocytes; Phagocytosis - drug effects; Plaque, Atherosclerotic - pathology; Science; Science (multidisciplinary); Swine; Translation; Vascular tissue
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52005-1

Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key ‘don’t-eat-me’ molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors. Systemic blockade of CD47 showed promising results for treating atherosclerosis but induces anemia. Here, the authors show that macrophage-specific nanoparticles promoting efferocytosis reduce apoptotic cell accumulation and inflammation in a porcine model of atherosclerosis without causing anemia.