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, the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)-b-poly(propylene sulfide) copolymers to enhance the targeted modulation of DCs by transporting the anti-inflammatory agent 1,25-dihydroxyvitamin D3-(aVD) and ApoB-100-derived antigenic peptide P210 are engineered. 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 enhance the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro. Weekly low-dose intravenous administration of DC-targeted, aVD-loaded polymersomes significantly inhibit atherosclerotic lesion development in high-fat-diet-fed ApoE−/− mice. The 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.
|Journal||Advanced Functional Materials|
|State||Published - Oct 1 2019|
Bibliographical noteFunding Information:
The authors would like to thank C. Reardon and G. Getz for advice, training, and protocols regarding the extraction and analysis of mouse aortas. The authors also thank J. Remis for CryoTEM assistance and the following facilities at Northwestern University: Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core; Center for Advanced Molecular Imaging; Biological imaging facility; Mouse Histology and Phenotyping Laboratory; Biological imaging facility and Keck-II facility of Northwestern University's NUANCE Center. This research was supported by the National Science Foundation CAREER Award (grant no. 1453576), the National Institutes of Health Director's New Innovator Award (grant no. 1DP2HL132390-01), American Heart Association (AHA) Postdoctoral Fellowship (17POST33670713), and the Louis A. Simpson & Kimberly K. Querrey Center for Regenerative Nanomedicine Regenerative Nanomedicine Catalyst Award.
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
- dendritic cells
- targeted delivery
ASJC Scopus subject areas
- Chemistry (all)
- Materials Science (all)
- Condensed Matter Physics