Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation

Jinyong Chen, Tanchen Ren (), Lan Xie, Haochang Hu, Xu Li, Miribani Maitusong, Xuhao Zhou, Wangxing Hu, Dilin Xu, Yi Qian, Si Cheng, Kaixiang Yu, Jian`an Wang () and Xianbao Liu ()
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Jinyong Chen: The Second Affiliated Hospital, Zhejiang University School of Medicine
Tanchen Ren: The Second Affiliated Hospital, Zhejiang University School of Medicine
Lan Xie: The Second Affiliated Hospital, Zhejiang University School of Medicine
Haochang Hu: The Second Affiliated Hospital, Zhejiang University School of Medicine
Xu Li: Zhongshan Hospital, Fudan University
Miribani Maitusong: The Second Affiliated Hospital, Zhejiang University School of Medicine
Xuhao Zhou: The Second Affiliated Hospital, Zhejiang University School of Medicine
Wangxing Hu: The Second Affiliated Hospital, Zhejiang University School of Medicine
Dilin Xu: The Second Affiliated Hospital, Zhejiang University School of Medicine
Yi Qian: The Second Affiliated Hospital, Zhejiang University School of Medicine
Si Cheng: The Second Affiliated Hospital, Zhejiang University School of Medicine
Kaixiang Yu: The Second Affiliated Hospital, Zhejiang University School of Medicine
Jian`an Wang: The Second Affiliated Hospital, Zhejiang University School of Medicine
Xianbao Liu: The Second Affiliated Hospital, Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790—an anti-calcification drug—to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr−/−) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.

Date: 2024
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DOI: 10.1038/s41467-024-44726-0

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