Bioinspired Anti‐VEGF Peptide Nanoparticle with Immune Regulating and Corneal Epithelium Penetration Capability for Corneal Neovascularization Therapy

ABSTRACT Corneal neovascularization (CorNV), a leading cause of blindness, is notoriously difficult to treat because of the cornea's tight epithelial barrier and the accompanying inflammatory environment. Current therapies suffer from poor penetration and inadequate management of inflammation. To overcome these challenges, we developed a novel bioinspired nanoparticle. A VEGF‐inhibiting peptide was co‐assembled with Cu ^{2 +} for stability and then modified with a reactive oxygen species (ROS) scavenger and a cell‐penetrating peptide. This multi‐functional design enables deep corneal penetration and targeted action. The resulting nanoparticle significantly prolongs ocular retention to 70 min. It achieved a remarkable penetration depth of 300 µm in a 3D corneal model, ensuring delivery to the site of disease. The nanoparticle demonstrated a dual mechanism of action; it effectively scavenged 60.31% of excess ROS and downregulated inflammation, reducing pro‐inflammatory macrophage polarization. This reshaped the immune microenvironment and potently suppressed angiogenesis, achieving 60.45% growth inhibition in the 3D model. In an animal model, the treatment successfully reduced abnormal blood vessel growth, with immunofluorescence confirming significantly lower expression of key inflammatory markers. This work presents a simple yet highly efficient strategy for deep ocular drug delivery, offering a potent therapeutic approach for CorNV and other oxidative stress‐ and inflammation‐related eye diseases.