Microglia-targeted delivery of MCC950 suppresses NLRP3–IL-18-mediated neuroinflammation and retinal injury in retinal vein occlusion

Retinal vein occlusion (RVO) causes retinal ischemia, macular edema, and vision loss, yet current anti-vascular endothelial growth factor (anti-VEGF) therapies primarily limit vascular leakage and leave ischemia-driven neuroinflammation insufficiently controlled. Here, we reveal a critical role for microglia-associated NLRP3–IL-18 signaling in amplifying inflammation during early RVO. Bulk retinal RNA sequencing showed broad innate immune activation, whereas single-cell transcriptomic profiling and spatial protein analysis identified prominent inflammasome-related changes in retinal microglia. Constitutive global deletion of Nlrp3 or Il18 attenuated microglial activation and preserved retinal structure and electrophysiological function. To translate this mechanistic insight into a targeted anti-inflammatory strategy, we engineered MG1-functionalized, MCC950-loaded nanoliposomes for microglia-targeted NLRP3 inhibition. MG1 functionalization promoted preferential nanoparticle uptake by activated microglia and suppressed NLRP3–IL-18 signaling more effectively than free MCC950 or non-targeted nanoliposomes. In experimental RVO, a single intravitreal dose administered 6 h after induction alleviated retinal inflammation and edema while preserving retinal electrophysiological responses. These findings establish microglia-associated NLRP3–IL-18 signaling as a therapeutic target in early RVO and support MG1-MCC950 nanoliposomes as a bioactive nanotherapeutic platform for RVO.