Charge-flip nanoparticles loaded with TAK1 inhibitors inhibit retinal neovascularization

Retinal neovascularization (RNV) is a key phenotype in multiple eye diseases that can cause blindness. Currently, the key treatment modality in RNV is the delivery of antivascular endothelial growth factor (anti-VEGF) medications via intravitreal injection, although the efficacy and adverse effects remain controversial. The aim of the present study was to investigate the influence of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) and charge-reversal triblock nanoparticles loaded with a TAK1 inhibitor on the formation of retinal neovascularization. First, through bioinformatics analysis of retinal fibrovascular membranes from proliferative diabetic retinopathy (PDR) patients and healthy retinal tissues, we identified TAK1, a crucial inflammation-related gene. We developed a charge-reversal PLGA-PEI-DMMA nanoparticle delivery system (poly@NG25) loaded with a TAK1 inhibitor. Using oxygen-induced retinopathy (OIR) mouse models and human umbilical vein endothelial cells (HUVECs) combined with methods such as CCK-8, EdU, and flow cytometry, we explored the role and mechanism. TAK1 was found to drive pathological neovascularization via inflammatory and angiogenic mediators. Compared with NG25 alone, poly@NG25 accelerates drug release in acidic environments; inhibits HUVECs proliferation, migration, and tube formation, promotes apoptosis, and more effectively reduces RNV and lesions in OIR mice with enhanced drug retention through the regulation of regulating relevant inflammatory and angiogenic factors. This study confirms that TAK1 is a key RNV therapeutic target and presents a pH-responsive charge-reversal poly@NG25 system, offering mechanistic insight and a new strategy for improving retinal vascular disease treatment.