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

doi:10.1016/j.bioactmat.2023.02.009

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

Bioact Mater. 2023 Feb 21:26:52-63. doi: 10.1016/j.bioactmat.2023.02.009. eCollection 2023 Aug.

Authors

Nisakorn Yodsanit^{1

2}, Takuro Shirasu³, Yitao Huang^{3

4}, Li Yin³, Zain Husain Islam³, Alexander Christopher Gregg³, Alessandra Marie Riccio³, Runze Tang³, Eric William Kent³, Yuyuan Wang^{1

2}, Ruosen Xie^{1

2}, Yi Zhao^{1

2}, Mingzhou Ye^{1

2}, Jingcheng Zhu^{1

2}, Yi Huang⁵, Nicholas Hoyt^{3

6}, Mengxue Zhang³, John A Hossack⁵, Morgan Salmon⁷, K Craig Kent³, Lian-Wang Guo³, Shaoqin Gong^{1

2}, Bowen Wang³

Affiliations

¹ Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
² Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, 53715, USA.
³ Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
⁴ The Biomedical Sciences Graduate Program (BIMS), School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
⁵ Department of Biomedical Engineering, School of Engineering, University of Virginia, Charlottesville, VA, 22908, USA.
⁶ School of Medicine and Health Sciences, George Washington University, Washington, DC, 20052, USA.
⁷ Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.

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.

Keywords: Abdominal aortic aneurysm; Biomimetic nanomedicine; ER stress; PERK; Targeted delivery.