Engineered Neutrophil Nanovesicles for Inhibiting Corneal Neovascularization by Synergistic Anti-Inflammatory, Anti-VEGF, and Chemoexcited Photodynamic Therapy.

Corneal neovascularization (CorNV) develops under various pathological conditions and is one of the main causes of blindness. Due to that CorNV progression involves multiple steps, anti-vascular endothelial growth factor (VEGF) drugs alone could not sufficiently suppress this process, highlighting an urgent need for an efficient delivery system for the multi-step management of CorNV. In this study, a neutrophil nanovesicle-based eye drop (NCCR) is developed for CorNV therapy that simultaneously inhibits angiogenesis and inflammation, while eliminating pathological cells through chemoexcited photodynamic therapy (PDT). NCCR targets inflammatory lesions by leveraging the expression of chemokine receptors from the source cells. Then, NCCR exerts inhibitory effects on the sequential steps of neovascularization. First, it acts as a decoy and exerts an anti-inflammatory effect by neutralizing cytokines via its receptors on the surface of nanovesicles. Second, thioketals bond-linked ranibizumab is released in the high reactive oxygen species microenvironment of CorNV sites to bind VEGF, inhibiting vascular endothelial cell activation and proliferation. Finally, chemoexcited PDT eliminates preformed corneal blood vessels, disrupting tube formation and pericyte recruitment. The synergistic effects of NCCR on angiogenesis and inflammation, combined with the induction of apoptosis in neovessels via chemoexcited PDT, offer a novel and efficient strategy for CorNV treatment.