ABSTRACT While anti-VEGF (vascular endothelial growth factor) therapy has been a watershed for the treatment of wet AMD (age-related macular degeneration), approximately 50% of patients receiving anti-VEGF therapy exhibit persistent disease activity, which can include persistent fluid exudation (edema), fibrosis, hemorrhage, and limited vision recovery. Blocking VEGF only addresses the formation of leaky and new vessels, but not fibrosis. Reducing fibrosis in concert with blocking leakiness and vessels may preserve vision and stop progression of neovascular AMD. Our long-term objective is to develop a translatable delivery system for AMD that can address the multifactorial nature of the disease and can be adjusted remotely via ultrasound for on-demand treatment as needed. Our objective in this project is to focus on the sustained delivery of two drugs that have been shown to address two of the critical components of wet AMD: neovascularization and fibrosis. We propose to deliver acriflavine, a HIF-1alpha inhibitor that prevents neovascularization in the eye, with pirfenidone, an antifibrotic drug, via a long-term delivery system based on polyurethane nanocapsules that deliver each drug over a prolonged period of time and can be triggered for on-demand release using ultrasound. We hypothesize that the controlled, long-term delivery of these two molecules in concert will lead to better, long-term outcomes including preservation of retinal tissue and visual acuity.