Hierarchically sequential targeting nanoplatform suppresses NETosis-promoted angiogenesis for corneal neovascularization therapy

Corneal neovascularization (CorNV) lacks effective therapies due to poor drug delivery and a complex inflammatory microenvironment, necessitating a deeper understanding of the underlying pathogenic mechanisms and the development of efficient delivery systems. Here we show that neutrophil extracellular traps (NETs) are pathologically activated in CorNV and identify peptidyl arginine deiminase 4 (PAD4) as a key therapeutic target. To achieve coordinated inhibition of NETosis and downstream vascular endothelial growth factor (VEGF) signaling, we engineer a reactive oxygen species (ROS) responsive copolymer encapsulating the PAD4 inhibitor Cl-amidine (Ca@PNH) that hierarchically targets neovascular endothelial cells and activated neutrophils via HRH and neutrophil elastase binding peptide (NEBP) peptides. Upon topical administration, Ca@PNH achieves prolonged ocular retention and lesion specific ROS triggered drug release, suppressing both NETs formation and angiogenesis. In a mouse CorNV model, this spatiotemporal strategy effectively treats neovascularization with excellent safety. Collectively, our work systematically establishes NETs as critical drivers of CorNV, identifies PAD4 as a druggable target, and offers a hierarchical delivery paradigm for inflammation driven ocular diseases.