Hierarchical ROS-scavenging hydrogel system for coordinating the modulation of RGC necroptosis and oxidative stress in an acute glaucoma model.

Glaucoma, a leading cause of irreversible blindness, is characterized by the progressive loss of retinal ganglion cells (RGCs). Beyond intraocular pressure (IOP)-dependent injury, IOP-independent pathways, specifically the self-amplifying axis between oxidative stress and the necroptotic cascade, are key drivers of disease progression. Mediated by the canonical RIPK1/RIPK3/MLKL signaling, necroptosis serves as a pivotal executioner of RGC loss. Oxidative stress functions as the critical upstream trigger that amplifies this cascade, forging a vicious cycle that demands a dual-targeted intervention strategy. To counteract this pathogenic axis, we developed a hierarchically responsive hydrogel (PD@Gel) by dispersing reactive oxygen species (ROS)-responsive Plantainoside D (PD)-loaded nanoparticles (PD@NPs) within a thiolated hyaluronic acid (HA-SH) precursor. Intravitreal injection triggers rapid in situ elation via dynamic disulfide cross-linking. The HA-SH matrix functions as a "macro-scavenger" to deplete extracellular ROS, while PD@NPs fabricated from thioether-functionalized polymers act as "ROS-capturing tentacles" to eliminate intracellular ROS and release PD. Released PD selectively inhibits the necroptotic cascade. In vitro, PD@Gel preserved mitochondrial membrane potential and attenuated necroptotic signaling, alleviating this vicious cycle. In vivo, a single intravitreal injection improved RGC survival, downregulated key necroptosis markers (p-RIPK1/p-MLKL), and partially restored visual function in a murine retinal ischemia-reperfusion (I/R) injury model. Thus, this macro-to-micro platform interferes with the self-amplifying oxidative stress-necroptosis axis, representing a potential neuroprotective strategy.