Enhanced Ocular Delivery of Beva via Ultra‐Small Polymeric Micelles for Noninvasive Anti‐VEGF Therapy

Abstract Pathological ocular neovascularization resulting from retinal ischemia constitutes a major cause of vision loss. Current anti‐VEGF therapies rely on burdensome intravitreal injections of Bevacizumab (Beva). Herein ultrasmall polymeric micelles encapsulating Beva (P@Beva) are developed for noninvasive topical delivery to posterior eye tissues. Beva is efficiently loaded into 11 nm micelles fabricated via self‐assembly of hyperbranched amphiphilic copolymers. The neutral, brush‐like micelles demonstrate excellent drug encapsulation and colloidal stability. In vitro, P@Beva enhances intracellular delivery of Beva in ocular cells versus free drug. Ex vivo corneal and conjunctival‐sclera‐choroidal tissues transport after eye drops are improved 23‐fold and 7.9‐fold, respectively. Anti‐angiogenic bioactivity is retained with P@Beva eliciting greater inhibition of endothelial tube formation and choroid sprouting over Beva alone. Remarkably, in an oxygen‐induced retinopathy (OIR) model, topical P@Beva matching efficacy of intravitreal Beva injection, is the clinical standard. Comprehensive biocompatibility verifies safety. Overall, this pioneering protein delivery platform holds promise to shift paradigms from invasive intravitreal injections toward simplified, noninvasive administration of biotherapeutics targeting posterior eye diseases.