Recombinant high-density lipoprotein targeted delivery of celastrol to promote foam cells lipophagy against early atherosclerosis

Introduction Atherosclerosis serving as the main underlying factor of cardiovascular disease (CVD) remains the primary cause of mortality and morbidity globally, while the deposition of massive cholesterol in macrophage-derived foam cells exerts pivotal roles in the occurrence and progression of atherosclerosis. Celastrol (CEL) is a bioactive ingredient owning potent capability to modulate lipid metabolism, whereas the poor bioavailability and potential toxicity limit its clinical application. Objectives This study aims to design a CEL-loaded recombinant high-density lipoprotein (rHDL) delivery platform for active targeting, which may effectively promote lipid degradation in foam cells and reversely transport excessive cholesterol to the liver for metabolism in time. Methods The rHDL loaded with CEL (CEL-rHDL) was prepared by the thin film dispersion method. Then the anti-atherosclerotic efficacy and targeted delivery to foam cells of atherosclerotic lesions were verified both in vitro and in vivo. RNA-sequence was applied to reveal the potential mechanism against early atherosclerosis, which was further validated through several molecular biology experiments. Results The prepared CEL-rHDL increased the targeting efficiency to foam cells of atherosclerotic lesions, mitigated its off-target toxicity, and improved anti-atherosclerotic efficacy. Importantly, CEL-rHDL decreased lipid storage in foam cells by triggering lipophagy via the activation of Ca 2+ /CaMKKβ/AMPK/mTOR signaling pathway and reverse cholesterol transport (RCT). Conclusion A combination of hypolipidemic chemo-intervention with rHDL participated specific and reverse delivery may offer a promising strategy for biocompatible treatment of early atherosclerosis. Graphical abstract