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Bioinspired PROTAC-induced macrophage fate determination alleviates atherosclerosis

Acta Pharmacologica Sinica volume 44, pages 1962–1976 (2023)Cite this article

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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Fig. 1: Development of the bioinspired PROTAC MELT and its PROTAC-induced macrophage fate determination for atherosclerosis therapy.
Fig. 2: Preparation and characterizations of MELT.
Fig. 3: Cellular uptakes of M2 macrophage membrane coated nanoparticles with CLSM images and FACS analysis.
Fig. 4: In vitro biosafety and biocompatibility evaluation of MELT.
Fig. 5: The evaluation of TRIM24 degradation and M2 macrophage polarization induced by MELT in vitro.
Fig. 6: The pharmacokinetics and aortic plaque targeting.
Fig. 7: The in vivo anti-atherosclerotic efficacy of MELT on ApoE−/− mice.
Fig. 8: Immunofluorescence analysis of the aortic root sections on ApoE−/− mice after different treatments.
Fig. 9: The in vivo biosafety evaluation of MELT on ApoE−/− mice. After 31 d of treatment, the mice were sacrificed, and the blood and tissues were collected, followed by biochemical analysis and H&E imaging.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (82072047, 81700382), Natural Science Foundation of Guangdong Province (2019A1515012166), Research Foundation of Education Bureau of Guangdong Province (2021ZDZX2004), Basic and Applied Basic Research Project of Guangzhou (202102080390), Outstanding Youth Development Program of Guangzhou Medical University, and The Open Research Funds from The Sixth Affiliated Hospital of Guangzhou Medical University/Qingyuan Peoples Hospital (202201-303).

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Author notes

  1. These authors contributed equally: Jiong-hua Huang, Chuang-jia Huang, Li-na Yu

Authors and Affiliations

  1. Department of Cardiology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, China

    Jiong-hua Huang, Chuang-jia Huang, Li-na Yu, Xiao-ling Guan, Lu Liang, Min-yan Wei & Ling-min Zhang

  2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Chuang-jia Huang, Xiao-ling Guan, Lu Liang, Min-yan Wei & Ling-min Zhang

  3. Department of Preventive Dentistry, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510013, China

    Li-na Yu

  4. The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, 511518, China

    Shang-wen Liang, Jian-hong Li & Ling-min Zhang

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Contributions

LL, MYW, and LMZ designed the study and supervised the project. JHH, CJH, and XLG performed the experiments and analyzed the data. SWL and JHL improved the protocol. LNY, LL, and MYW wrote the draft. MYW and LMZ also worked on the data analysis and final manuscript preparation. The authors reviewed and approved the published version of the manuscript.

Corresponding authors

Correspondence to Lu Liang, Min-yan Wei or Ling-min Zhang.

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Huang, Jh., Huang, Cj., Yu, Ln. et al. Bioinspired PROTAC-induced macrophage fate determination alleviates atherosclerosis. Acta Pharmacol Sin 44, 1962–1976 (2023). https://doi.org/10.1038/s41401-023-01088-5

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