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.