A boronate-phenolic network nanoplatform carrying dimethyl itaconate for ameliorating neovascular age-related macular...

Age-related macular degeneration (AMD), particularly its neovascular form driven by choroidal neovascularization (CNV), remains leading cause of irreversible blindness worldwide. Current anti-vascular endothelial growth factor (VEGF) therapy offers limited efficacy, indicating that monotherapies targeting the downstream VEGF pathway cannot meet clinical needs, thus highlighting the demand for upstream and multifunctional therapeutic strategies. In this study, a boronate-phenolic network was constructed by cross-linking antioxidant tannic acid (TA) with ((1,3,5-Triazine-2,4,6-triyl)tris(benzene-4,1-diyl))triboronic acid (TBPT), in the presence of polyethylene glycol (PEG) for stabilization. Anti-inflammatory dimethyl itaconate (DMI) was further encapsulated, resulting in DTTP nanoparticles. With this multifunctional design, DTTP effectively promoted ROS elimination and mitochondrial protection, reestablished glutathione homeostasis, and downregulated genes involved in pyroptotic and inflammatory pathways. In a laser-induced CNV mouse model, intravitreal DTTP exhibited robust therapeutic efficacy with a favorable safety profile, achieving a 71.8% reduction in neovascularization and a 57.4% reduction in vascular leakage, with aflibercept serving as a clinically relevant benchmark. Collectively, DTTP represents a promising multifunctional nanotherapeutic for the management of neovascular AMD (nAMD).