ROS-responsive drug delivery system with enhanced anti-angiogenic and anti-inflammatory properties for neovascular age-related macular degeneration therapy

Neovascular age-related macular degeneration (nAMD) has become the leading cause of vision loss in people over 60 years old. Anti-vascular endothelial growth factor (anti-VEGF), the current first-line drug for the treatment of nAMD, suffers from poor patient compliance and fundus fibrosis scar formation. In addition to VEGF, oxidative stress and inflammation also play key roles in the pathological process of choroidal neovascularization (CNV). Therefore, combinational therapeutics with anti-angiogenic, reactive oxygen species (ROS)-scavenging and anti-inflammatory functions will broaden therapeutic effects and reduce side effects. The Yes-associated protein-1 (YAP) has proven to inhibit angiogenesis, inflammation, and subretinal fibrosis in CNV. Herein, verteporfin (VP), the inhibitor of YAP, was encapsulated into a polydopamine modified mesoporous silica nanoparticle (PMSN-VP NPs) and then conjugated with PLGA-PEG-PBA decorated cerium oxide nanoparticles (PPCeO₂ NPs) to develop an integrated nano-drug delivery system. The PMSN-VP@PPCeO₂ NPs exhibited ROS-responsive degradation and VP release behaviors, and our in vitro data revealed that the PMSN-VP@PPCeO₂ NPs downregulated angiogenic-related and fibrosis-related gene expressions in human umbilical vein endothelial cells (HUVECs) and further showed excellent anti-oxidative and anti-inflammatory capacities in BV2 cells. More importantly, the PMSN-VP@PPCeO₂ NPs significantly suppressed vascular leakage and macrophage infiltration in the laser-induced CNV lesions of mice. Overall, our findings demonstrated that the PMSN-VP@PPCeO₂ NPs provided an effective therapeutic strategy for nAMD.