Ultrahigh‐Efficacy VEGF Neutralization Using Carbonized Nanodonuts: Implications for Intraocular Anti‐Angiogenic Therapy

Abstract Ocular angiogenesis, associated with diseases such as retinopathy of prematurity and diabetic retinopathy, is a leading cause of irreversible vision loss. Herein, carbon nanodonuts (CNDs) with a donut‐shaped structure are synthesized using sodium alginate (SA) and 1,8‐diaminooctane (DAO) through a one‐step thermal process. The formation of SA/DAO‐CNDs occurs through a crosslinking reaction between SA and DAO, creating amide bonds followed by partial carbonization. In human retinal pigment epithelial cells exposed to H 2 O 2 or lipopolysaccharide, the SA/DAO‐CNDs display a more than fivefold reduction in reactive oxygen species and proinflammatory cytokines, such as IL‐6 and IL‐1β, when compared to carbonized nanomaterials produced exclusively from SA. Furthermore, the CNDs effectively inhibit vascular endothelial growth factor A‐165 (VEGF‐A 165 )‐induced cell migration and tube formation in human umbilical vein endothelial cells due to their strong affinity for VEGF‐A 165 , with a dissociation constant of 2.2 × 10 −14 M , over 1600 times stronger than the commercial drug bevacizumab (Avastin). Trypsin digestion coupled with LC‐MS/MS analysis reveals that VEGF‐A 165 interacts with SA/DAO‐CNDs through its heparin‐binding domain, leading to activity loss. The SA/DAO‐CNDs demonstrate excellent biocompatibility and potent anti‐angiogenic effects in chicken embryos and rabbit eyes. These findings suggest that SA/DAO‐CNDs hold promise as a therapeutic agent for treating various angiogenesis‐related ocular diseases.