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

Nisakorn Yodsanit; Takuro Shirasu; Yitao Huang; Li Yin; Zain Husain Islam; Alexander Christopher Gregg; Alessandra Marie Riccio; Runze Tang; Eric William Kent; Yuyuan Wang; Ruosen Xie; Yi Zhao; Mingzhou Ye; Jingcheng Zhu; Yi Huang; Nicholas Hoyt; Mengxue Zhang; John A. Hossack; Morgan Salmon; K. Craig Kent; Lian-Wang Guo; Shaoqin Gong; Bowen Wang

Bioactive Materials (Aug 2023)

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

Nisakorn Yodsanit,
Takuro Shirasu,
Yitao Huang,
Li Yin,
Zain Husain Islam,
Alexander Christopher Gregg,
Alessandra Marie Riccio,
Runze Tang,
Eric William Kent,
Yuyuan Wang,
Ruosen Xie,
Yi Zhao,
Mingzhou Ye,
Jingcheng Zhu,
Yi Huang,
Nicholas Hoyt,
Mengxue Zhang,
John A. Hossack,
Morgan Salmon,
K. Craig Kent,
Lian-Wang Guo,
Shaoqin Gong,
Bowen Wang

Affiliations

Nisakorn Yodsanit: Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA; Department of Ophthalmology and Visual Sciences, 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; The Biomedical Sciences Graduate Program (BIMS), 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; Department of Ophthalmology and Visual Sciences, 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; Department of Ophthalmology and Visual Sciences, 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; Department of Ophthalmology and Visual Sciences, 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; Department of Ophthalmology and Visual Sciences, 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; Department of Ophthalmology and Visual Sciences, 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; School of Medicine and Health Sciences, George Washington University, Washington, DC, 20052, 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; Corresponding author.
Shaoqin Gong: Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA; Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, 53715, USA; Corresponding author. 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; Corresponding author.

Journal volume & issue: Vol. 26
pp. 52 – 63

Abstract

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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.

Published in Bioactive Materials

ISSN: 2452-199X (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Technology: Electrical engineering. Electronics. Nuclear engineering: Materials of engineering and construction. Mechanics of materials; Science: Biology (General)
Website: https://www.keaipublishing.com/en/journals/bioactive-materials/

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