Macrophage membrane orientated enveloping β-cyclodextrin nano-assemblies for enhancing cholesterol efflux from atherosclerotic plaques

Excess cholesterol in macrophages is progressively converted into cholesterol crystals (CCs), promoting the transformation of macrophages into foam cells, a key process that drives the development of atherosclerosis (AS). β-cyclodextrin (β-CD) is a potent solubilizer of CCs and has been shown that could promote the efflux of CCs from foam cells. However, β-CD randomized extracts cholesterol in vivo, which reduces the therapeutic effect for AS plaque lesion and biosafety. Here, we constructed phosphatidylserine-targeting peptide (PS peptide) modified polyethylene glycol (PEG)-CD and ferrocene-modified phenylboronic acid (Fc-PBA) as a reactive oxygen species (ROS)-responsive switch (“OFF-ON”). Under physiological condition, Fc of Fc-PBA effectively closes the cavity of β-CD and loads resveratrol (RVT) via borate bonds (RVT NPs). The PS peptide on the surface of nanoparticles was conjugated with the phosphatidylserine on the inner leaflet of macrophage membrane (MM) to harvest the right-side-out biomimetic membrane camouflaged nanoparticles (MM@RVT NPs), which could enhance the delivery to the inflammatory sites of AS plaques. When MM@RVT NPs arrived the plaque, the breakdown of MM@RVT NPs resulting from the oxidation of Fc-PBA, restored the β-CD lumen to dissolve CCs into free cholesterol and enhanced its efflux. Moreover, RVT was timely released to further enhance the expression of receptors associated with mediating cholesterol efflux. Besides, RVT also reduced the oxidative stress, and promoted the phenotypic conversion of macrophages from M1 to M2 type for alleviating inflammation in AS lesions. Therefore, MM@RVT NPs could be an intelligent nanoplatform for promoting the efficient AS management.