Surface Engineered Polymersomes for Enhanced Modulation of Dendritic Cells During Cardiovascular Immunotherapy

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.