Project Summary Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with high lethality upon aneurysm rupture, which is particularly prevalent in the aged population. Surgical repairs, albeit invasive and risky, remain the only treatment option, with no pharmacotherapies clinically available. Thus, there is a compelling unmet clinical need to discover non-invasive strategies to slow down or even reverse the progression of AAA lesions. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods. A growing body of evidence reveals that degenerative smooth muscle cells (SMCs) orchestrate AAA pathogenesis and progression. The dying SMCs incite deleterious dialogues with endothelial cells and macrophages, weakening the aortic wall while propagating inflammation. Our exciting preliminary data indicates that the Protein Kinase R-like ER Kinase (PERK) arm of the endoplasmic reticulum (ER) stress response pathway is a potent driver of SMC degeneration and hence a potential target for AAA intervention. We found that either pharmacological inhibition or genetic silencing of PERK blocked SMC degeneration and ameliorated mitochondrial dysfunction in vitro. Moreover, SMC-specific deletion of PERK profoundly reduced the incidence of aortic aneurysm as well as the rupture risk in an angiotensin (Ang)II model in male mice. Importantly, we also conceived a biomimetic, reactive oxygen species (ROS)-detonable, and size-tunable “cluster bomb” nanodesign that uniquely caters to AAA-targeted delivery of versatile therapeutic payloads, either hydrophobic PERK inhibitors or siRNAs. This platelet membrane coated nanoplatform demonstrated excellent AAA homing, aortic wall penetration, and when loaded with a selective PERK inhibitor, halted the progression of pre-existing AAA lesions in a murine model induced by elastase challenge. These preliminary findings and published evidence lead to our central hypothesis: PERK is a key driver of SMC degeneration and AAA pathology; and PERK-targeting therapy — enabled through a multi- modal “cluster bomb” nanoplatform — can lead to effective stabilization or even regression of pre-existing AAA lesions. To test this hypothesis, we will determine the specific role of PERK in SMC degeneration and the underlying mechanisms such as PERK-mediated mitochondrial dysfunction (Aim 1a), as well as its role in the onset and propagation of experimental AAA in two distinct murine models (Aim 1b). We will also develop highly innovative multi-modal “cluster bomb” nanoplatforms to encapsulate PERK small molecule inhibitors (Aim-2a) or siRNAs (Aim-2b) and evaluate their utility for PERK-targeting AAA therapies in murine models. Thus, a unique strength of this proposal is the combined innovations in both drug target and delivery method. The ultimate product will be a new paradigm in non-invasive management of AAA, which is expected to significantly reduce th...