期刊
ADVANCED FUNCTIONAL MATERIALS
卷 29, 期 42, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201904399
关键词
atherosclerosis; dendritic cells; immunotherapy; polymersomes; targeted delivery
类别
资金
- National Science Foundation CAREER Award [1453576]
- National Institutes of Health Director's New Innovator Award [1DP2HL132390-01]
- American Heart Association (AHA) Postdoctoral Fellowship [17POST33670713]
- Louis A. Simpson & Kimberly K. Querrey Center for Regenerative Nanomedicine Regenerative Nanomedicine Catalyst Award
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.
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