Hierarchical ROS-scavenging hydrogel system for coordinating the modulation of RGC necroptosis and oxidative stress...

Area of Science:

• Ophthalmology
• Neuroscience
• Biomaterials Science

Background:

• Glaucoma causes irreversible blindness through retinal ganglion cell (RGC) death.
• IOP-independent pathways, including oxidative stress and necroptosis, drive RGC loss.
• The RIPK1/RIPK3/MLKL pathway executes RGC death, amplified by oxidative stress.

Purpose of the Study:

• To develop a dual-targeted intervention strategy against the oxidative stress-necroptosis axis in glaucoma.
• To create a hierarchically responsive hydrogel (PD@Gel) for intravitreal delivery.

Main Methods:

• Dispersing Plantainoside D (PD)-loaded nanoparticles (PD@NPs) in thiolated hyaluronic acid (HA-SH) to form PD@Gel.
• Utilizing dynamic disulfide cross-linking for in situ gelation after intravitreal injection.
• Employing HA-SH as an extracellular ROS scavenger and PD@NPs for intracellular ROS capture and PD release.

Main Results:

• In vitro studies showed PD@Gel preserved mitochondrial potential and reduced necroptotic signaling.
• In vivo, a single intravitreal injection improved RGC survival in a murine retinal ischemia-reperfusion (I/R) model.
• The treatment downregulated necroptosis markers (p-RIPK1/p-MLKL) and partially restored visual function.

Conclusions:

• The PD@Gel system effectively interferes with the self-amplifying oxidative stress-necroptosis axis.
• This macro-to-micro platform demonstrates potential as a neuroprotective strategy for glaucoma.
• Targeting both oxidative stress and necroptosis offers a promising therapeutic avenue for RGC protection.