Foam cells with the pro-inflammatory macrophage phenotype (M1) play an essential role in
atherosclerosis progression. Either cellular
cholesterol removal or drug intervention was reported to polarize M1 into the anti-inflammatory phenotype (M2) for
atherosclerosis regression. These might be realized simultaneously by drug-loaded discoidal reconstituted
high-density lipoproteins (d-rHDLs) with the functions of cellular
cholesterol efflux and targeted drug delivery on macrophages. However,
cholesterol reception can drive the remodelling of d-rHDLs, which serves to release drugs specifically in the
atherosclerotic plaque but might incur premature drug leakage in blood circulation. Given that, the proposed strategy is to inhibit the remodelling behaviour of the carrier in blood circulation and responsively accelerate it under the atherosclerotic microenvironmental stimulus. Herein,
atorvastatin calcium-loaded d-rHDL was modified by a PEGylated
ferrocene/β-
cyclodextrin supramolecular copolymer (PF/TC) to construct ROS-responsive PF/TC-AT-d-rHDL, which is expected to possess plasma stability and biosafety as well as triggered drug release by
cholesterol efflux promotion. As a result, PF/TC-AT-d-rHDL could responsively dissemble into β-
cyclodextrin modified AT-d-rHDL under the ROS-triggered dissociation of PF/TC, therefore exhibiting increased
cholesterol efflux from the
cholesterol donor and drug release through the remodelling behaviour of the carrier in vitro. Moreover, PF/TC-AT-d-rHDL enhanced cellular
cholesterol removal in foam cells after response to ROS, inhibiting intracellular
lipid deposition compared with other d-rHDL carriers. Interestingly, cellular drug uptake was significantly promoted upon cellular
cholesterol removal by restoring the permeability and fluidity of foam cell membranes as indicated by flow cytometry and fluorescence polarization analysis, respectively. Importantly, compared with untreated foam cells, PF/TC-AT-d-rHDL obviously increased the ratio of M2/M1 by 6.3-fold, which was even higher than the effect of PF/TC-d-rHDL (3.4-fold) and free drugs (1.9-fold), revealing that PF/TC-AT-d-rHDL synergistically promoted the M2 polarization of macrophages. Accordingly, PF/TC-AT-d-rHDL boosted the secretion of anti-inflammatory
cytokines and inhibited that of inflammatory
cytokines. Collectively, PF/TC-AT-d-rHDL exerted synergistic M2 polarization effects on foam cells for atherosclerotic
immunomodulatory therapy via responsively mediating
cholesterol efflux and delivering drugs.