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

  • J Nanobiotechnology. 2025 Mar 22;23(1):237. doi: 10.1186/s12951-025-03327-9.
Yang Li  1 ,  Xiaoxia Xue  1 ,  Liuchunyang Yu  1 ,  Jinxiu Qian  1 ,  Xiaoyu Li  1 ,  Meng Tian  1 ,  Jue Yang  1 ,  Rongjun Deng  1 ,  Cheng Lu  2 ,  Cheng Xiao  3 ,  Yuanyan Liu  4
Affiliations
  • 1. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
  • 2. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China. [email protected].
  • 3. Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China. [email protected].
  • 4. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China. [email protected].
PMID: 40119460 DOI: 10.1186/s12951-025-03327-9
Abstract

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 CA2+/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.

Keywords
Atherosclerosis; Celastrol; Lipophagy; Targeted delivery; rHDL.
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