Pro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis
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.
Authors
- Changhao Fu (ORCID: https://orcid.org/0000-0001-7568-3369)
- Yapei Zhang (ORCID: https://orcid.org/0000-0002-1607-8385)
- Lingfeng Luo (ORCID: https://orcid.org/0000-0002-0601-0053)
- Lars Mäegdefessel (ORCID: https://orcid.org/0000-0001-5228-2634)
- Shaunak Adkar (ORCID: https://orcid.org/0000-0002-8893-2413)
- Nicholas J. Leeper (ORCID: https://orcid.org/0000-0002-0905-2806)
- Nicolás López (ORCID: https://orcid.org/0000-0003-0659-4500)
- Sharika Bamezai (ORCID: https://orcid.org/0000-0002-2944-740X)
- Gayatri Suresh Kumar (ORCID: https://orcid.org/0000-0003-4636-7740)
- Ferhaan Ahmad (ORCID: https://orcid.org/0000-0003-2877-4641)
- Jianqin Ye (ORCID: https://orcid.org/0000-0003-4492-3897)
- Mozhgan Lotfi
- Caitlin Bell (ORCID: https://orcid.org/0000-0001-7352-142X)
- Bryan Ronain Smith (ORCID: https://orcid.org/0000-0002-5990-2901)
- Ryan B Choi (ORCID: https://orcid.org/0000-0003-2980-3977)
- Sesha L. A. Paluri (ORCID: https://orcid.org/0000-0002-7612-5235)
- Romila Manchanda (ORCID: https://orcid.org/0000-0003-1619-0374)
- Susan Walsh (ORCID: https://orcid.org/0000-0002-7064-1589)
- Fudi Wang (ORCID: https://orcid.org/0000-0001-8730-0003)
- Manisha Kumari (ORCID: https://orcid.org/0000-0001-7870-6896)
- Yoko Kojima (ORCID: https://orcid.org/0000-0001-9814-2282)
- Alice Ingelsson
- Tom Alsaigh (ORCID: https://orcid.org/0009-0003-1037-302X)
- Leo Barrios
- Zach Miller
- Madhu Puri
Institutions
- University of Iowa (US)
- Cardiovascular Institute of the South (US)
- TUM Klinikum (DE)
- Karolinska Institutet (SE)
- Quantitative BioSciences (US)
- German Centre for Cardiovascular Research (DE)
- Stanford Medicine (US)
- Michigan State University (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1038/s41467-024-52005-1
- Citations
- 23
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 5.53
Funders
- Foundation for the National Institutes of Health
- American Heart Association
- Falk Foundation
- Dr. Ralph and Marian Falk Medical Research Trust
- Sarnoff Cardiovascular Research Foundation
- National Institutes of Health