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Bioinspired PROTAC-induced macrophage fate determination alleviates atherosclerosis
Jiong-Hua Huang1, Chuang-Jia Huang1,2, Li-Na Yu1,3
1Department of Cardiology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, China.
Insights
This study introduces MELT, a novel PROTAC delivery system that targets M1 macrophages to degrade TRIM24, promoting M2 polarization and reducing atherosclerosis plaque formation for effective cardiovascular disease treatment.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Nanomedicine
Background:
- Atherosclerosis, driven by lipid accumulation and inflammation, causes plaque buildup and arterial stenosis, posing significant health risks.
- Current treatments for atherosclerosis plaque face limitations, highlighting the need for novel therapeutic strategies.
- Pro-inflammatory M1 macrophages are key players in atherosclerosis development, while TRIM24 inhibits anti-inflammatory M2 macrophage polarization.
Purpose of the Study:
- To develop a targeted drug delivery system for atherosclerosis treatment using bioinspired nanoparticles.
- To investigate the efficacy of a Proteolysis-Targeting Chimera (PROTAC) degrader targeting TRIM24 for M2 macrophage polarization.
- To evaluate the therapeutic potential of M2 macrophage membrane-coated nanoparticles loaded with a PROTAC degrader (dTRIM24) for atherosclerosis.
Main Methods:
- Construction of bioinspired PROTAC nanoparticles (MELT) by coating dTRIM24-loaded PLGA nanoparticles with M2 macrophage membrane.
- Characterization of MELT for morphology, size, and stability, assessing its specificity towards M1 macrophages and acid-responsive drug release.
- Intravenous administration of MELT in high-fat, high-cholesterol diet-fed ApoE-/- mice to evaluate plaque accumulation and therapeutic effects.
Main Results:
- MELT demonstrated enhanced specificity for M1 macrophages and controlled release of dTRIM24 in acidic environments.
- In vivo studies showed significant MELT accumulation in atherosclerotic plaques, targeting M1 macrophages.
- Effective TRIM24 degradation by MELT induced M2 macrophage polarization, leading to a notable reduction in plaque formation and atherosclerosis progression.
Conclusions:
- MELT represents a promising bioinspired therapeutic agent for targeted atherosclerosis treatment.
- The study provides an effective strategy for targeted therapy by modulating macrophage polarization to alleviate atherosclerosis.
- This approach offers potential for developing novel treatments to combat cardiovascular disease progression.
Abstract:
Atherosclerosis is a major cause of death and disability in cardiovascular disease. Atherosclerosis associated with lipid accumulation and chronic inflammation leads to plaques formation in arterial walls and luminal stenosis in carotid arteries. Current approaches such as surgery or treatment with statins encounter big challenges in curing atherosclerosis plaque. The infiltration of proinflammatory M1 macrophages plays an essential role in the occurrence and development of atherosclerosis plaque. A recent study shows that TRIM24, an E3 ubiquitin ligase of a Trim family protein, acts as a valve to inhibit the polarization of anti-inflammatory M2 macrophages, and elimination of TRIM24 opens an avenue to achieve the M2 polarization. Proteolysis-targeting chimera (PROTAC) technology has emerged as a novel tool for the selective degradation of targeting proteins. But the low bioavailability and cell specificity of PROTAC reagents hinder their applications in treating atherosclerosis plaque. In this study we constructed a type of bioinspired PROTAC by coating the PROTAC degrader (dTRIM24)-loaded PLGA nanoparticles with M2 macrophage membrane (MELT) for atherosclerosis treatment. MELT was characterized by morphology, size, and stability. MELT displayed enhanced specificity to M1 macrophages as well as acidic-responsive release of dTRIM24. After intravenous administration, MELT showed significantly improved accumulation in atherosclerotic plaque of high fat and high cholesterol diet-fed atherosclerotic (ApoE-/-) mice through binding to M1 macrophages and inducing effective and precise TRIM24 degradation, thus resulting in the polarization of M2 macrophages, which led to great reduction of plaque formation. These results suggest that MELT can be considered a potential therapeutic agent for targeting atherosclerotic plaque and alleviating atherosclerosis progression, providing an effective strategy for targeted atherosclerosis therapy.
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