Engineering Microenvironment-Responsive Nanobiomaterials for Precision Therapy of Fundus Neovascular Diseases

Abstract Fundus neovascular diseases (FNDs) cause irreversible visual impairment through pathological angiogenesis, vascular leakage, inflammation, oxidative injury, and barrier breakdown. Current anti-vascular endothelial growth factor (VEGF) therapy has greatly improved disease control, but repeated intraocular injections, incomplete responses, recurrent exudation, and limited tissue repair remain major challenges. Beyond VEGF signaling, FNDs are shaped by a dynamically remodeled lesion microenvironment that contains abnormal vascular interfaces, activated endothelium, infiltrating immune cells, elevated reactive oxygen species, glucose-related metabolic stress, and matrix metalloproteinase activity. These pathological cues create opportunities for microenvironment-responsive nanobiomaterials that actively adapt to diseased fundus tissues. By integrating biomimetic recognition, ligand-guided targeting, immune-cell guidance, redox-responsive chemistry, glucose-regulated systems, enzyme-cleavable structures, and active transport modules, responsive nanocarriers can improve lesion localization, spatiotemporal cargo release, and microenvironmental modulation. This review discusses emerging nanocarrier strategies for FNDs according to angiogenic, inflammatory oxidative, and barrier-remodeling cues, and highlights their potential to advance ocular nanomedicine toward precise, durable, and multifunctional fundus therapy.