Abstract

Autoimmune uveitis is a sight-threatening inflammatory disease in which the cGAS-STING signaling pathway exacerbates inflammation by recognizing excessive cell-free DNA (cfDNA). However, conventional cfDNA scavengers have limited blood-retinal barrier penetration, and monotherapies cannot control the complex inflammatory network. Herein, we developed a cationic poly(disulfide)-drug nanoplatform (LA/DexP), which self-assembled via salt bridge interactions and aggregation-induced polymerization between a guanidyl-functionalized lipoic acid derivative (LA) and dexamethasone phosphate (DexP). This platform is designed to synergistically inhibit the cGAS-STING pathway and achieve efficient intraocular drug delivery. LA/DexP functioned as an efficient scavenger of cfDNA through electrostatic interaction, thereby inhibiting cGAS-STING overactivation. Meanwhile, it leveraged thiol-disulfide exchange to enhance blood-retinal barrier penetration, achieving a 5.09-fold higher apparent permeability coefficient than free DexP, and exhibited ROS-responsive drug release. In an experimental autoimmune uveitis mouse model, LA/DexP treatment significantly reduced cfDNA levels and inhibited cGAS-STING signaling. It also downregulated pro-inflammatory cytokine expression, promoted macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, and rebalanced Th1/Th17-Treg cell subsets. These combined effects effectively inhibited uveitis severity. In summary, this study establishes a highly barrier-permeable nanoplatform that synergistically integrates drug delivery with cGAS-STING pathway inhibition, offering a promising therapeutic strategy for autoimmune uveitis.