Conformationally Variable Peptides Trap and Detoxify Ox‐LDL in Plaques for Attenuating Atherosclerosis in Multiple Species
Abstract
ABSTRACT Cardiovascular and cerebrovascular events due to atherosclerosis (AS) are the leading causes of mortality worldwide. Current therapeutic strategies failed to simultaneously target lipid deposition, chronic inflammation, and endothelial dysfunction. Herein, we developed BIFD, a conformationally variable peptide targeting lysophosphatidylcholine (LPC) on oxidized low‐density lipoproteins (ox‐LDL), which binds ox‐LDL to form nanoaggregates, blocking ox‐LDL toxicity, reducing inflammation, promoting metabolism/excretion of ox‐LDL in macrophage. In addition, both ox‐LDL specifically distributed in plaque sites and the targetability of BIFD to ox‐LDL enable the BIFD targetability to plaque of AS. Therefore, rapamycin (Rapa), an anti‐inflammatory drug, is designed to be encapsulated into BIFD to form Rapa@BIFD nanoparticles (NPs). Rapa@BIFD may target plaque, enhancing accumulation and retention of Rapa@BIFD on the AS lesion. Consequently, Rapa@BIFD demonstrated high efficacy against AS with minimal side effects. In vitro and in vivo studies in apolipoprotein E‐knockout murine and canine models revealed that Rapa@BIFD effectively reduced oxidative damage, and inflammatory responses, while promoting lipid metabolism and excretion. Rapa@BIFD mitigated side effects of Rapa, such as hyperlipidemia and splenic toxicity. These findings present a transformative multitarget for AS, combining efficacy with minimal side effects and enhanced clinical translatability.
Article Details
Authors (21)
Hong‐Mei Zhao
Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
Jun‐Ye Chen
Department of Vascular Surgery Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
Qi‐Lin Liang
CAS Center for Excellence in Nanoscience CAS Key Laboratory For Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology (NCNST) Beijing China
Xi‐Xi Dong
Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
Ying Fan
Guo‐Yang Xu
CAS Center for Excellence in Nanoscience CAS Key Laboratory For Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology (NCNST) Beijing China
Danhua Chen
Jing‐Xian Huang
CAS Center for Excellence in Nanoscience CAS Key Laboratory For Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology (NCNST) Beijing China
Jia‐Huan He
Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
Jia‐Qi Feng
CAS Center for Excellence in Nanoscience CAS Key Laboratory For Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology (NCNST) Beijing China
Ke‐Qiang Shu
Department of Vascular Surgery Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
Yu Zeng
Yun‐Fei Xue
Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
Kai Song
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Organic Solids, Institute of Chemistry
Lin Wang
Jing Wang
Hunan Cancer Hospital Changsha China
Kai Yue
Xin‐Xin Zhang
School of Energy and Environment Engineering University of Science and Technology Beijing Beijing China
Hua Zhang
Lei Wang
Hao Wang
Division of Quantitative Sciences, Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland USA