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LDL-binding IL-10 reduces vascular inflammation in atherosclerotic mice

Nature Biomedical Engineering (2026)Cite this article

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Abstract

Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here we engineer IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we construct Fab-IL-10 by fusing IL-10 to the antibody fragment (Fab) of four different oxidized LDL-binding antibodies. We show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques in atherosclerosis mouse models. Among them, 2D03-IL-10 significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This modular technology may be applied to a variety of protein therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.

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Fig. 1: Fusing IL-10 to an LDL-binding antibody fragment enables lipoprotein binding while maintaining signalling and anti-inflammatory properties.
Fig. 2: Fab-IL-10 constructs have increased plasma half-lives and tissue bioavailability in apoE−/− mice fed HFD for 10 weeks.
Fig. 3: 2D03-IL-10 reduces immune cell infiltration into the aorta of apoE−/− mice fed HFD.
Fig. 4: 2D03-IL-10 binds immune cells and co-localizes with foamy macrophages.
Fig. 5: 2D03-IL-10 binding to LDL is generalizable to multiple contexts.

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Data availability

Source data for the main results of this study are available in the Supplementary Information. Additional unprocessed data are available from the corresponding authors upon request. Source data are provided with this paper.

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Acknowledgements

This work was supported by the Chicago Immunoengineering Innovation Center of the University of Chicago, the Gracias Family Foundation, the National Heart, Lung and Blood Institute (T32HL007605-35, L.R.V.), the American Heart Association Postdoctoral Fellowship Award (#916845, L.R.V.) and the NIH T32 MSTP Training Grants (#T32GM150375 and #T32GM007281, S.N.d.M.). We thank C. R. Alulis for helpful conversations regarding murine atherosclerosis models; S. Gomes for tissue culture and general laboratory support; the Cytometry and Antibody Technology Core Facility (Cancer Center Support Grant P30CA014599), the Animal Resources Center, the Human Tissue Resource Center, and the Integrated Light Microscopy Core at the University of Chicago. Figures were created with BioRender.com.

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Authors and Affiliations

  1. Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA

    Lisa R. Volpatti, Salvador Norton de Matos, Gustavo Borjas, Taryn N. Beckman, Joseph W. Reda, Elyse A. Watkins, Zhengjie Zhou & Jeffrey A. Hubbell

  2. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA

    Lisa R. Volpatti

  3. Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA

    Lisa R. Volpatti

  4. Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA

    Salvador Norton de Matos

  5. Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, IL, USA

    Taryn N. Beckman & Yun Fang

  6. Department of Medicine, University of Chicago, Chicago, IL, USA

    Zhengjie Zhou & Yun Fang

  7. Animal Resources Center, University of Chicago, Chicago, IL, USA

    Mindy Nguyen & Ani Solanki

  8. Committee on Immunology, University of Chicago, Chicago, IL, USA

    Jeffrey A. Hubbell

  9. Committee on Cancer Biology, University of Chicago, Chicago, IL, USA

    Jeffrey A. Hubbell

  10. Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, New York, NY, USA

    Jeffrey A. Hubbell

  11. Departments of Biology and Chemistry, Faculty of Arts and Science, New York University, New York, NY, USA

    Jeffrey A. Hubbell

  12. Department of Biochemistry and Molecular Pharmacology, Grossman School of Medicine, NYU Langone Health, New York, NY, USA

    Jeffrey A. Hubbell

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Contributions

L.R.V. conceptualized the project, designed the methodology, performed validation, formal analysis, investigation, data curation and visualization, supervised and administered the project, acquired funding and wrote the original manuscript draft. S.N.d.M. designed the methodology and software, performed validation, formal analysis, investigation and visualization, and reviewed and edited the manuscript. G.B. designed the methodology and software, conducted formal analysis and investigation, and reviewed and edited the manuscript. T.N.B. designed the methodology, conducted formal analysis and investigation, and reviewed and edited the manuscript. J.W.R. designed the methodology, conducted investigation, and reviewed and edited the manuscript. E.A.W. designed the methodology, conducted investigation, procured resources, and reviewed and edited the manuscript. Z.Z. designed the methodology, conducted investigation, and reviewed and edited the manuscript. M.N. designed the methodology, conducted investigation, and reviewed and edited the manuscript. A.S. designed the methodology, conducted investigation, and reviewed and edited the manuscript. Y.F. designed the methodology, procured resources, supervised the project, and reviewed and edited the manuscript. J.A.H. conceptualized the project, procured resources, supervised and administered the project, acquired funding, and reviewed and edited the manuscript.

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Correspondence to Lisa R. Volpatti or Jeffrey A. Hubbell.

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Nature Biomedical Engineering thanks Prediman Shah and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Volpatti, L.R., Norton de Matos, S., Borjas, G. et al. LDL-binding IL-10 reduces vascular inflammation in atherosclerotic mice. Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-025-01573-8

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