Prophylactic self-assembled nucleic acid hydrogel targeting retinal ganglion cell cuproptosis and microglial neuroinflammation for retinal ischemia-reperfusion injury

Retinal ischemia-reperfusion (RIR) injury constitutes a common pathological pathway in glaucoma, diabetic retinopathy, and other neurodegenerative diseases, frequently leading to irreversible neuronal loss. This study identifies concurrent FDX1-dependent retinal ganglion cell (RGC) cuproptosis and MyD88-mediated microglial inflammation as key drivers of retinal neurodegeneration in RIR. To address this, we developed SAH-CIM, a self-assembled nucleic acid hydrogel for sustained co-delivery of si<i>Fdx1</i> and si<i>Myd88</i>. SAH-CIM effectively suppressed RGC cuproptosis via FDX1 knockdown and reduced pro-inflammatory cytokines by inhibiting the MyD88/TRAF6/NF-κB pathway. In murine RIR models, prophylactic SAH-CIM administration preserved 25.3% more retinal ganglion cells than free siRNA controls, with structural integrity confirmed by histological analysis and optical coherence tomography. Functional recovery was evidenced by electroretinography and visual cliff tests, with SAH-CIM treated mice showing 36.6% reduced time on the cliff side. Crucially, the dual-targeting design demonstrated significantly superior therapeutic efficacy over single-target approaches. The highly biocompatible and self-assembled SAH-CIM presents a promising prophylactic resolution for RIR-related diseases with broad translational potential.