Synchronous Reactive Oxygen Species Scavenging and Immunomodulation for Autoimmune Uveitis Therapy by a Mannosylated Biomimetic Nanocloak.

Abstract

Autoimmune uveitis is a recurrent, vision-threatening inflammatory disease that demands precise and ongoing treatment. However, current therapies have limitations in ocular targeting, in controlling reactive oxygen species (ROS), and in regulating key inflammatory pathways. In this study, we develop a mannosylated biomimetic nanocloak (H-151-Cu/Zn-MOF@LM@Man) that combines active targeting, ROS scavenging, and STING pathway inhibition for a synergistic approach to treating autoimmune uveitis. This nanoplatform consists of a copper-zinc bimetallic metal-organic framework (Cu/Zn-MOF) loaded with the STING antagonist H-151 and coated with a hybrid membrane made from macrophage-derived membranes and mannosylated liposomes (LM@Man). After systemic injection, the nanocloak passively homes to inflamed tissues through membrane camouflage and actively targets mannose receptor-expressing immune cells. It efficiently crosses the blood-retinal barrier (BRB) and accumulates at intraocular lesions. At the inflammation site, the Cu/Zn-MOF core scavenges excess ROS using nanozyme activity. At the same time, H-151 inhibits the STING-TBK1-NF-κB pathway, reshaping macrophage and microglia phenotypes, and restoring immune balance. This closed-loop system effectively reduces inflammatory cytokine production, lessens tissue damage, and enhances therapeutic precision. Overall, this study presents a multifunctional, translatable nanoplatform that enables targeted delivery, redox control, and immune reprogramming─offering a promising strategy for treating autoimmune uveitis and other inflammation-related disorders.