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Polypyridiniums with Inherent Autophagy-Inducing Activity for Atherosclerosis Treatment by Intracellularly
Mengxiao Liang1, Qian Wang2, Song Zhang1
1South China Advanced Institute for Soft Matter Science and Technology, School of Emergent Soft Matter, South China University of Technology, Guangzhou, 510640, China.
Abstract:
Atherosclerosis is a chronic inflammatory disease of the arterial intima and is becoming the leading cause of morbidity and mortality worldwide. There is considerable evidence that defective autophagy and overproduction of reactive oxygen species (ROS) are closely involved in the development and progression of atherosclerosis. Here, a polymer is developed with the inherent autophagy-inducing activity to treat atherosclerosis by co-delivering antioxidant enzymes. The lead material P5c screened from a library of polypyridiniums shows robust efficacy in cytosolic protein delivery, and efficiently delivers superoxide dismutase (SOD) and catalase (CAT) into macrophages to down-regulate intracellular ROS. Moreover, P5c activates autophagy in macrophages and sufficiently inhibits foam cell formation. The P5c nanoparticle loaded with both SOD and CAT is further coated with neutrophil membranes to treat atherosclerosis in an ApoE-/- mice model. The treatment exhibits potent anti-atherosclerosis effect via activating autophagy, decreasing the infiltration of senescent cells in atherosclerotic plaques, regulating the M2 polarization of macrophages, and restoring the structure and function of splenic corpuscles. The polymer offers a multifaceted approach to combat atherosclerosis, addressing both cellular dysfunction and the need for targeted protein delivery within affected cells.
Insights
A novel polymer P5c treats atherosclerosis by activating autophagy and delivering antioxidant enzymes to reduce reactive oxygen species (ROS). This approach effectively inhibits foam cell formation and reduces plaque progression in mice.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cardiovascular Research
Background:
- Atherosclerosis is a leading global cause of death, characterized by chronic arterial inflammation.
- Defective autophagy and excessive reactive oxygen species (ROS) are key contributors to atherosclerosis development and progression.
Purpose of the Study:
- To develop a novel polymer-based therapeutic strategy for atherosclerosis.
- To investigate the efficacy of a polymer (P5c) in co-delivering antioxidant enzymes and inducing autophagy in macrophages.
Main Methods:
- Screening of polypyridinium compounds to identify P5c for protein delivery.
- Utilizing P5c nanoparticles to deliver superoxide dismutase (SOD) and catalase (CAT) into macrophages.
- Evaluating P5c's effect on autophagy, ROS levels, and foam cell formation in vitro.
- Testing neutrophil membrane-coated P5c nanoparticles loaded with SOD and CAT in an ApoE-/- atherosclerosis mouse model.
Main Results:
- P5c demonstrated efficient cytosolic protein delivery and ROS down-regulation in macrophages.
- P5c successfully activated autophagy and inhibited foam cell formation.
- The nanoparticle treatment in mice showed significant anti-atherosclerosis effects.
- Therapeutic outcomes included reduced senescent cell infiltration, modulated macrophage polarization, and restored splenic corpuscle structure.
Conclusions:
- The developed polymer P5c offers a multifaceted therapeutic approach for atherosclerosis.
- Targeted delivery of antioxidant enzymes combined with autophagy induction presents a promising strategy.
- This approach addresses cellular dysfunction and protein delivery challenges in treating atherosclerosis.
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