Plaque‐Hepatic Targeting Nanotherapy Disrupts the PCSK9‐LOX‐1 Axis to Suppress oxLDL in Atherosclerosis
- 1Department of Ultrasound Xinhua Hospital School of Medicine Shanghai Jiao Tong University Shanghai China
- 2State Key Laboratory of Systems Medicine For Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China
- 3Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering East China University of Science and Technology Shanghai China
Abstract
Atherosclerosis remains the leading cause of cardiovascular mortality, with elevated oxidized low‐density lipoprotein (oxLDL) as a key driver. oxLDL metabolism involves two critical steps: generation mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9)‐induced LDLR degradation, and plaque uptake via lectin‐like oxLDL receptor‐1 (LOX‐1). Current PCSK9 inhibitors reduce oxLDL production but show limited effects on plaque oxLDL uptake and inflammation. Thus, synergistic strategies targeting both steps are urgently needed. To address this, we developed a hepatic‐plaque targeting nanoparticle, siPCSK9@PEAL NPs‐aL, based on a PEG‐PLGA‐PLL framework. The nanoparticle was surface‐functionalized with anti‐LOX‐1 antibody for plaque targeting. Concurrently, optimized particle size enabled hepatic accumulation while minimizing clearance by the reticuloendothelial system (RES), facilitating effective hepatic delivery of siPCSK9. The PLGA core allowed controlled siRNA release, and the cationic PLL layer promoted efficient condensation and protection. In vitro, this system effectively silenced PCSK9, downregulated LOX‐1, rescued mitochondrial function and reduced apoptosis. In advanced atherosclerosis mice, weekly administration significantly reduced aortic plaque burden, stabilized plaque composition, and normalized serum lipid levels. Lipidomics showed oxLDL‐associated lipid downregulation and metabolic networks remodeling. Taken together, this dual‐targeting nanodrug integrates systemic lipid‐lowering with local anti‐inflammatory effects by simultaneously inhibiting oxLDL generation and utilization, offering a promising precision therapeutic strategy for atherosclerosis.
Related
- Stable Phosphonate Inhibitors of Elastase LasB Suppress Pseudomonas aeruginosa Virulence via Zinc-Targeting Pyrrolidone Scaffolds
- Copper‐Doped Prussian Blue Nanozymes With Hyaluronic Acid‐Mediated Targeting Alleviate Oxidative Stress and Regulate Cholesterol Handling for Atherosclerosis Therapy
- Deciphering Nano–Bio Interactions of Hyaluronic Acid-Clove Carbon Dots for Multifunctional Endodontic Nanotherapy
- A bibliometric analysis of global research trends in tumor microenvironment based nanotherapy.
- Surface adsorbates suppress low-frequency noise for shallow nitrogen-vacancy centers
BibTeX
@article{duan2026plaquehepatic,
title = {{Plaque‐Hepatic Targeting Nanotherapy Disrupts the PCSK9‐LOX‐1 Axis to Suppress oxLDL in Atherosclerosis}},
author = {Yi Duan and Yijie Qiu and Yan Zhu and Quan Wang and Jiangtao Lin and Yourong Duan and Qi Wang and Yi Dong},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77100},
url = {https://doi.org/10.1002/advs.77100},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Plaque‐Hepatic Targeting Nanotherapy Disrupts the PCSK9‐LOX‐1 Axis to Suppress oxLDL in Atherosclerosis
AU - Yi Duan
AU - Yijie Qiu
AU - Yan Zhu
AU - Quan Wang
AU - Jiangtao Lin
AU - Yourong Duan
AU - Qi Wang
AU - Yi Dong
PY - 2026
DA - 2026/08/13
JO - Advanced Science
DO - 10.1002/advs.77100
UR - https://doi.org/10.1002/advs.77100
AB - Atherosclerosis remains the leading cause of cardiovascular mortality, with elevated oxidized low‐density lipoprotein (oxLDL) as a key driver. oxLDL metabolism involves two critical steps: generation mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9)‐induced LDLR degradation, and plaque uptake via lectin‐like oxLDL receptor‐1 (LOX‐1). Current PCSK9 inhibitors reduce oxLDL production but show limited effects on plaque oxLDL uptake and inflammation. Thus, synergistic strategies targeting both steps are urgently needed. To address this, we developed a hepatic‐plaque targeting nanoparticle, siPCSK9@PEAL NPs‐aL, based on a PEG‐PLGA‐PLL framework. The nanoparticle was surface‐functionalized with anti‐LOX‐1 antibody for plaque targeting. Concurrently, optimized particle size enabled hepatic accumulation while minimizing clearance by the reticuloendothelial system (RES), facilitating effective hepatic delivery of siPCSK9. The PLGA core allowed controlled siRNA release, and the cationic PLL layer promoted efficient condensation and protection. In vitro, this system effectively silenced PCSK9, downregulated LOX‐1, rescued mitochondrial function and reduced apoptosis. In advanced atherosclerosis mice, weekly administration significantly reduced aortic plaque burden, stabilized plaque composition, and normalized serum lipid levels. Lipidomics showed oxLDL‐associated lipid downregulation and metabolic networks remodeling. Taken together, this dual‐targeting nanodrug integrates systemic lipid‐lowering with local anti‐inflammatory effects by simultaneously inhibiting oxLDL generation and utilization, offering a promising precision therapeutic strategy for atherosclerosis.
SN - 2198-3844
ER -