Disrupting the Oxidative Stress–Inflammation–Corneal Neovascularization Cycle with Ultrasmall Nanoparticles

Abstract

ABSTRACT Corneal neovascularization (CoNV) is a primary contributor to corneal scarring and vision impairment. During its initiation and progression, inflammatory reactions and oxidative stress synergistically trigger a pathological vicious cycle of oxidative stress, inflammation, and angiogenesis, posing a severe therapeutic challenge. In this study, a noninvasive transepithelial therapeutic strategy using ultrasmall polydopamine nanoparticles (UPDA NPs) with triple effects is developed. Their unique small size, approximately 3 nm, greatly enhances their radical‐scavenging capability and facilitates superior transepithelial delivery. Extensive research demonstrated that the obtained UPDA NPs possess excellent anti‐inflammatory, antioxidant, and anti‐angiogenic properties. By scavenging reactive oxygen species (ROS), activating the nuclear factor erythroid 2–related factor 2 (NRF2) antioxidant pathway, and suppressing multiple proangiogenic signaling cascades, they can disrupt the pathological cycle of inflammation, oxidative stress, and neovascularization at molecular, cellular, and animal levels. In an alkali‐burned mouse model, UPDA NPs notably reduce CoNV area and length, accelerate corneal repair, and exhibit no local or systemic toxicity, providing a new nanomedicine with translational potential for precise treatment of CoNV.