Surface engineered polymersomes for enhanced modulation of dendritic cells during cardiovascular immunotherapy

Sijia Yi; Xiaohan Zhang; Hussain Sangji; Yugang Liu; Sean D Allen; Baixue Xiao; Sharan Bobbala; Cameron L Braverman; Lei Cai; Peter I Hecker; Mathew DeBerge; Edward B Thorp; Ryan E Temel; Samuel I Stupp; Evan A Scott

doi:10.1002/adfm.201904399

Surface engineered polymersomes for enhanced modulation of dendritic cells during cardiovascular immunotherapy

Adv Funct Mater. 2019 Oct 17;29(42):1904399. doi: 10.1002/adfm.201904399. Epub 2019 Aug 12.

Authors

Sijia Yi^{1

2}, Xiaohan Zhang¹, Hussain Sangji^{1

2}, Yugang Liu¹, Sean D Allen³, Baixue Xiao¹, Sharan Bobbala¹, Cameron L Braverman¹, Lei Cai⁴, Peter I Hecker^{4

5}, Mathew DeBerge^{6

7}, Edward B Thorp^{6

7}, Ryan E Temel^{4

5}, Samuel I Stupp^{1

8

9

10

11}, Evan A Scott^{1

2

3

11}

Affiliations

¹ Department of Biomedical Engineering, Northwestern University, IL 60208.
² Chemistry of Life Processes Institute, Northwestern University, IL 60208.
³ Interdisciplinary Biological Sciences, Northwestern University, IL 60208.
⁴ Saha Cardiovascular Research Center, University of Kentucky, KY 40536, USA.
⁵ Department of Pharmacology and Nutritional Sciences, University of Kentucky, KY 40536, USA.
⁶ Department of Pathology, Northwestern University Feinberg School of Medicine, IL 60611, USA.
⁷ Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, IL 60611, USA.
⁸ Department of Materials Science and Engineering, Northwestern University, IL 60208.
⁹ Department of Chemistry, Northwestern University, IL 60208.
¹⁰ Department of Medicine, Northwestern University Feinberg School of Medicine, IL 60611, USA.
¹¹ Simpson Querrey Institute, Northwestern University Feinberg School of Medicine, IL 60611, USA.

Abstract

The principle cause of cardiovascular disease (CVD) is atherosclerosis, a chronic inflammatory condition characterized by immunologically complex fatty lesions within the intima of arterial vessel walls. Dendritic cells (DCs) are key regulators of atherosclerotic inflammation, with mature DCs generating pro-inflammatory signals within vascular lesions and tolerogenic DCs eliciting atheroprotective cytokine profiles and regulatory T cell (Treg) activation. Here, we engineered the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)-b-poly(propylene sulfide) copolymers to selectively target and modulate DCs by transporting the anti-inflammatory agent 1, 25-Dihydroxyvitamin D3 (aVD) and ApoB-100 derived antigenic peptide P210. Polymersomes decorated with an optimized surface display and density for a lipid construct of the P-D2 peptide, which binds CD11c on the DC surface, significantly enhanced the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro. Intravenous administration of the optimized polymersomes achieved selective targeting of DCs in atheroma and spleen compared to all other cell populations, including both immune and CD45^- cells, and locally increased the presence of tolerogenic DCs and cytokines. aVD-loaded polymersomes significantly inhibited atherosclerotic lesion development in high fat diet-fed ApoE^-/- mice following 8 weeks of administration. Incorporation of the P210 peptide generated the largest reductions in vascular lesion area (~33%, p<0.001), macrophage content (~55%, p<0.001), and vascular stiffness (4.8-fold). These results correlated with an ~6.5-fold increase in levels of Foxp3⁺ regulatory T cells within atherosclerotic lesions. Our results validate the key role of DC immunomodulation during aVD-dependent inhibition of atherosclerosis and demonstrate the therapeutic enhancement and dosage lowering capability of cell-targeted nanotherapy in the treatment of CVD.

Keywords: atherosclerosis; dendritic cell; immunotherapy; polymersome; targeted delivery.

Abstract

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