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Induction of Accelerated Atherosclerosis in Mice: The "Wire-Injury" Model
Published on: August 25, 2020
Pathological Mechanism-Inspired Biomimetic Nano-Senotherapy for Reversing Experimental Atherosclerosis in ApoE-/-
Yuhan Tian1, Yanrui Yang2, Qiuyu Li1
1College of Pharmacy and Food, Key Laboratory of Research and Application of Ethnic Medicine Processing and Preparation on the Qinghai-Tibet Plateau, Southwest Minzu University, Chengdu, China.
Abstract:
The greatest challenge in atherosclerosis (AS) management lies in achieving lesion reversal, not merely slowing progression. Senescent cell accumulation-driven by continuous generation and apoptotic resistance-perpetuates plaque pathology and obstructs regression. This study addresses the reversal conundrum through a dual-action strategy: blocking new senescent cell formation while enhancing clearance of existing senescent cells. We developed a ROS-responsive dimeric prodrug (K2A) from the MPO-inhibitory tripeptide KYC, which co-assembles with the senolytics Navitoclax into a nano-Senotherapy (N@K2A). Further cloaked with neutrophil membranes from AS mice, the biomimetic N@K2A@NEM precisely targets plaques, responds to local ROS, and orchestrates senescent cell formation and removal. This targeted senotherapeutic intervention demonstrates effective reversal of established experimental AS, offering a potential solution to the field's most pressing clinical dilemma.
Insights
This study introduces a novel senotherapy that targets and clears senescent cells in atherosclerosis (AS) plaques. This dual-action approach effectively reverses established AS lesions, addressing a key challenge in disease management.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Nanomedicine
Background:
- Atherosclerosis (AS) progression is significantly driven by senescent cell accumulation, hindering plaque regression.
- Current AS management strategies often focus on slowing disease progression rather than achieving lesion reversal.
Purpose of the Study:
- To develop a targeted senotherapeutic strategy for effective reversal of established atherosclerosis.
- To investigate a dual-action approach that inhibits new senescent cell formation and promotes clearance of existing senescent cells.
Main Methods:
- Development of a ROS-responsive dimeric prodrug (K2A) from a myeloperoxidase (MPO)-inhibitory tripeptide (KYC).
- Co-assembly of K2A with Navitoclax into a senotherapeutic nanoparticle (N@K2A).
- Biomimetic cloaking of nanoparticles with neutrophil membranes (N@K2A@NEM) for targeted delivery to atherosclerotic plaques.
Main Results:
- The biomimetic nano-senotherapy (N@K2A@NEM) precisely targets atherosclerotic plaques.
- The therapy responds to local reactive oxygen species (ROS) within plaques.
- Demonstrated effective reversal of established experimental atherosclerosis in vivo.
Conclusions:
- Targeted senolytic intervention offers a promising strategy for reversing established atherosclerosis.
- This dual-action senotherapy addresses the critical clinical challenge of achieving atherosclerotic lesion reversal.
