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

作     者：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 

作者机构：Department of Biomedical EngineeringWisconsin Institute for DiscoveryUniversity of Wisconsin-MadisonMadisonWI53715USA Department of Ophthalmology and Visual SciencesUniversity of Wisconsin-MadisonMadisonWI53715USA Department of SurgerySchool of MedicineUniversity of VirginiaCharlottesvilleVA22908USA The Biomedical Sciences Graduate Program(BIMS)School of MedicineUniversity of VirginiaCharlottesvilleVA22908USA Department of Biomedical EngineeringSchool of EngineeringUniversity of VirginiaCharlottesvilleVA22908USA School of Medicine and Health SciencesGeorge Washington UniversityWashingtonDC20052USA Department of Cardiac SurgeryMichigan MedicineUniversity of MichiganAnn ArborMI48109USA 

出 版 物：《Bioactive Materials》 (生物活性材料（英文）)

年 卷 期：2023年第26卷第8期

页      面：52-63页

核心收录：

学科分类：0831[工学-生物医学工程（可授工学、理学、医学学位）] 07[理学] 070205[理学-凝聚态物理] 0805[工学-材料科学与工程（可授工学、理学学位）] 0702[理学-物理学] 

基　　金：supported by the National Institute of Health(NIH)grants R01HL133665(to L.-W.G.),R01HL143469 R01HL129785(to K.C.K,S.G.,and L.-W.G.) R01HL162895(to B.W.) R01HL132395 and 1S10RR027333(to J.A.H.) Overseas Research Fellowships,The Uehara Memorial Foundation in Japan(to T.S.). 

主　　题：Abdominal aortic aneurysm ER stress PERK Biomimetic nanomedicine Targeted delivery 

摘      要：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.