An Aggregation‐Induced Polymerization Poly(Disulfide)‐Drug Nanoplatform for Autoimmune Uveitis Therapy via Inhibiting the cGAS‐STING Pathway

作者：Yuelan Wu, Wenbo Geng, Qinjin Dai, Wanyun Zhang, Yuxian Lai, Pei Zhang, Chunjiang Zhou, Yinuo Wang, Qingfeng Cao, Xiang Luo, Yujie Lai, Changwei Huang, Peizeng Yang · 发表于：Advanced Science · 年份：2026 · DOI：10.1002/advs.76813 · 研究领域：interferon and immune responses、Ocular Diseases and Behçet’s Syndrome、Nanoplatforms for cancer theranostics

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 stu...