Project Summary Aortic aneurysms (AA) are degenerative diseases characterized by dilation caused by arterial wall microarchitecture destruction. AAs are a life-threatening condition with the potential to lead to dissection, rupture, and even fatality. High blood pressure, atherosclerosis, and smoking increase the risk of AA initiation and rupture. Some inherited connective tissue disorders, such as Marfan, Loeys-Dietz, or Ehlers-Danlos syndromes, can also increase the risk for AA. Due to procedural risks, surgical intervention is only recommended for large aneurysms or those with a high rate of growth. However, several small aneurysms rupture while many larger ones never do. As many as 90% of detected AAAs are small and do not meet the surgical criteria; these patients are “watchfully waiting” without any treatment. Currently, no pharmacological approaches are available to stop AAA progression. We have developed a novel nanoparticle (NP) delivery system conjugated with a unique elastin antibody that targets only degraded vascular elastin, a hallmark of all aneurysms, named DESTINeD. We have discovered elastin stabilizing and regeneration potential of polyphenol-pentagalloyl glucose (PGG) when delivered with DESTINeD. We hypothesize that increasing the strength of the aneurysmal aorta by stabilizing residual elastin and collagen and regenerating lost elastin will prevent the expansion and rupture of AAs. In Specific Aim 1, we will use an abdominal aortic rupture mouse models (Angiotensin II infusion with either intraperitoneal injection of TGF-b neutralizing antibody or adding β Aminopropionitrile, BAPN in drinking water) to test if rupture can be prevented using DESTIENeD therapy and whether arterial homeostasis will be restored and inflammation reduced. In Specific Aim 2, we will test the hypothesis that degraded elastin-targeting PGG- loaded nanoparticles can prevent aneurysm rupture in a mouse model of Marfan Syndrome. Marfan syndrome is caused by mutation of the fibrillin-1 gene that causes dysfunctional elastin deposition in connective tissues, and many of these patients develop severe cardiovascular complications such as thoracic AAs. Fbn1R/R homozygote mice develop ubiquitous aortic elastin fragmentation, an inflammatory-fibroproliferative response, and inflammation-mediated elastolysis so that 99% die of aortic rupture between 2-6 months of age. Here we will test if our nanoparticle therapy can stabilize elastin and collagen and repair ECM and prevent aneurysmal rupture and death. As a preclinical proof for our therapy, a swine model of the abdominal AA will be used in Specific Aim 3 to test if DESTINeD nanoparticles, with a humanized elastin antibody, would arrest growth and reverse existing AAs. If successful, ours will be the first injectable therapy that can be translated to prevent aortic dilation and rupture.