Abstract

Atherosclerosis is the main pathological basis of cardiovascular disease and urgently requires more effective and targeted therapies. Here, we present a cholesterol-modulated macrophage membrane–mimetic nanoplatform for rapamycin delivery, in which β-cyclodextrin is employed to selectively deplete cholesterol from donor cell membranes. Cholesterol depletion significantly improves nanoparticle uptake by inflammatory macrophages, potentially through enhanced membrane fluidity and preserved key receptor–ligand interactions. In vitro , the cholesterol-depleted nanomedicines promote foam cell cholesterol efflux and suppress pro-inflammatory cytokine secretion, with therapeutic efficacy increasing as membrane cholesterol content decreases. In vivo , the resulting “slimming” membrane–coated nanoparticles exhibit enhanced immune evasion, prolonged systemic circulation, and improved plaque targeting, while maintaining excellent biosafety. In atherosclerotic mice, treatment with these nanoparticles reduces plaque area and lipid accumulation while increasing collagen content in a membrane cholesterol–dependent manner, indicating therapeutic effects and enhanced plaque stability. Notably, these benefits are achieved without altering systemic lipid levels, suggesting a primarily lesion-localized mechanism of action. Collectively, this study demonstrates that the “slimming” membrane–mimetic nanoplatform offers a promising approach for precise, inflammation-targeted therapy of atherosclerosis and may be extended to other chronic inflammatory vascular disorders. Graphical abstract