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

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.