Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms

Nisakorn Yodsanit, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Takuro Shirasu, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Yitao Huang, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Li Yin, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Zain Husain Islam, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Alexander Christopher Gregg, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Alessandra Marie Riccio, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Runze Tang, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Eric William Kent, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Yuyuan Wang, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Ruosen Xie, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Yi Zhao, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Mingzhou Ye, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Jingcheng Zhu, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Yi Huang, Department of Biomedical Engineering, School of Engineering, University of Virginia, Charlottesville, VA, 22908, USA.
Nicholas Hoyt, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Mengxue Zhang, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
John A. Hossack, Department of Biomedical Engineering, School of Engineering, University of Virginia, Charlottesville, VA, 22908, USA.
Morgan Salmon, Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
K Craig Kent, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Lian-Wang Guo, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Shaoqin Gong, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Bowen Wang, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.

Document Type

Journal Article

Publication Date

8-1-2023

Journal

Bioactive materials

Volume

26

DOI

10.1016/j.bioactmat.2023.02.009

Keywords

Abdominal aortic aneurysm; Biomimetic nanomedicine; ER stress; PERK; Targeted delivery

Abstract

Abdominal aortic aneurysm (AAA) is a progressive aortic dilatation, causing ∼80% mortality upon rupture. Currently, there is no approved drug therapy for AAA. Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which, however, account for ∼90% of the newly diagnosed cases. It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods. There is substantial evidence that degenerative smooth muscle cells (SMCs) orchestrate AAA pathogenesis and progression. In this study, we made an exciting finding that PERK, the endoplasmic reticulum (ER) stress Protein Kinase R-like ER Kinase, is a potent driver of SMC degeneration and hence a potential therapeutic target. Indeed, local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo. In parallel, we also conceived a biomimetic nanocluster (NC) design uniquely tailored to AAA-targeting drug delivery. This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating; and when loaded with a selective PERK inhibitor (PERKi, GSK2656157), the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA. In summary, our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis, but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

Department

School of Medicine and Health Sciences Student Works

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