Responsive Multi-Arm PEG-Modified COF Nanocomposites: Dynamic Photothermal, pH/ROS Dual-Responsive, Targeted Carriers for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic immune disease characterized by the infiltration of immune cells and the proliferation of fibroblast-like synoviocytes (FLS) at the joint site, leading to inflammation and joint destruction. However, the available treatment options targeting both inflammatory and proliferative FLS are limited. Herein, we present three covalent organic frameworks (COFs) photothermal composite systems modified with multi-armed PEG for the treatment of RA. These systems exhibited a dual response under low pH and high reactive oxygen species (ROS) conditions at the site of inflammation, with a specific focus on delivering the protein drug ribonuclease A (RNase A). This protein, in combination with photothermal therapy, effectively targeted and eliminated FLS while reducing ROS production by immune cells. Notably, molecular docking studies revealed the interaction between RNase A and NF-κB p65 protein, and Western blotting confirmed its inhibitory effect on NF-κB activity. In vitro and in vivo experiments verified the significant reduction in joint swelling and deformities in adjuvant-induced arthritis (AIA) rats after treatment with RNase A delivered by multi-armed PEG-modified COF ligands, restoring joint morphology to normal. In vivo plasma indices demonstrated the ability of this treatment to scavenge and reduce pro-inflammatory cytokines while maintaining a favorable biosafety profile. These findings underscore the promising therapeutic potential of COFs for the treatment of RA, highlighting their unique capabilities in addressing both inflammatory and proliferative aspects of the disease and expanding the scope of biomedical applications for COFs. This article is protected by copyright. All rights reserved.