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

Sharika Bamezai, Yapei Zhang, Manisha Kumari, Mozhgan Lotfi, Tom Alsaigh, Lingfeng Luo, Gayatri Suresh Kumar, Fudi Wang, Jianqin Ye, Madhu Puri, Romila Manchanda, Sesha Paluri, Shaunak S. Adkar, Yoko Kojima, Alice Ingelsson, Caitlin F. Bell, Nicolas G. Lopez, Changhao Fu, Ryan B. Choi, Zach Miller, Leo Barrios, Susan Walsh, Ferhaan Ahmad, Lars Maegdefessel, Bryan Ronain Smith () and Nicholas J. Leeper ()
Additional contact information
Sharika Bamezai: Stanford University School of Medicine
Yapei Zhang: Michigan State University
Manisha Kumari: Michigan State University
Mozhgan Lotfi: Stanford University School of Medicine
Tom Alsaigh: Stanford University School of Medicine
Lingfeng Luo: Stanford University School of Medicine
Gayatri Suresh Kumar: Stanford University School of Medicine
Fudi Wang: Stanford University School of Medicine
Jianqin Ye: Stanford University School of Medicine
Madhu Puri: Michigan State University
Romila Manchanda: Michigan State University
Sesha Paluri: Michigan State University
Shaunak S. Adkar: Stanford University School of Medicine
Yoko Kojima: Stanford University School of Medicine
Alice Ingelsson: Stanford University School of Medicine
Caitlin F. Bell: Stanford University School of Medicine
Nicolas G. Lopez: Stanford University School of Medicine
Changhao Fu: Stanford University School of Medicine
Ryan B. Choi: Stanford University School of Medicine
Zach Miller: Michigan State University
Leo Barrios: Michigan State University
Susan Walsh: University of Iowa Carver College of Medicine
Ferhaan Ahmad: University of Iowa Carver College of Medicine
Lars Maegdefessel: Technical University
Bryan Ronain Smith: Michigan State University
Nicholas J. Leeper: Stanford University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52005-1

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