Sterically Controlled Cyclobutane-Dioxetane Ultrabright Afterglow Nanosystem for Cyclic Therapy of Choroidal Neovascularization in Mice

Afterglow occurring after light excitation ceases offers a safer light source to the laser-activated verteporfin therapy approved by the FDA for choroidal neovascularization (CNV). However, conventional afterglow molecules, especially adamantane-dioxetanes with high steric hindrance, exhibit limited chemiexcitation, restricting electron transfer and diminishing therapeutic effects. Here, we constructed ultrabright afterglow nanosystems by integrating low-hindrance cyclobutane moieties into the dioxetane framework. Among these cyclobutane substituents, the benzyl oxocyclobutane-dioxetane is the brightest afterglow molecule due to its lowest hindrance, showing 35.7 times faster relative chemiexcitation rate and 59 times higher afterglow intensity than adamantane-dioxetane, alongside a three-order-of-magnitude increase in total afterglow emission. Consequently, at the equivalent concentration, the benzyl oxocyclobutane-dioxetane-based nanosystem produces nearly five times more singlet oxygen than free verteporfin. In a CNV mouse model, cyclic treatment with our nanosystem reduced lesion areas by 64.9%, outperforming the 39.3% reduction achieved by free verteporfin counterpart. By eliminating the need for laser activation, this strategy minimizes ocular damage, providing a safe and effective treatment for CNV and other retinal disorders.