Bilirubin-polymer nanocarriers enable targeted farrerol delivery for glaucoma neuroprotection via Nrf2-mediated ferroptosis/apoptosis inhibition

Glaucoma, a leading cause of irreversible blindness, is characterized by progressive retinal ganglion cell (RGC) degeneration with limited treatment options. The natural flavonoid farrerol exhibits neuroprotective potential through antioxidative and anti-inflammatory effects, but its therapeutic application is limited by poor bioavailability and photodegradation. This study investigates farrerol's neuroprotective mechanisms and develops an optimized nanoformulation for enhanced efficacy. In vitro oxygen-glucose deprivation/reperfusion (OGD/R) and in vivo ischemia-reperfusion (IR) models demonstrate that farrerol significantly improves RGC survival and visual function. Mechanistic studies reveal that farrerol activates the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway, reduces reactive oxygen species (ROS) accumulation, and modulates key ferroptosis markers (glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4)), thereby inhibiting RGC apoptosis. To overcome delivery limitations, farrerol-loaded bilirubin nanoparticles (FB-NPs) are developed, showing enhanced stability and neuroprotective effects in glaucomatous injury models. These findings identify the Nrf2/ferroptosis/apoptosis axis as a novel therapeutic target and present an effective nanodelivery strategy for glaucoma treatment. Schematic illustration of FB-NPs delivering farrerol to activate Nrf2 pathway and inhibit RGC degeneration. • Established glaucoma models; farrerol protects R28 cells and RGCs, and improves visual function. • Farrerol activates Nrf2, reduces ROS, and modulates ferroptosis/apoptosis to alleviate injury. • A ROS-responsive nanodelivery system (FB-NPs) enhances farrerol bioavailability, stability, and neuroprotection.