A ROS-Responsive Supramolecular Peptide Hydrogel Attenuates Rheumatoid Arthritis by Modulating Synoviocyte Activity and Inflammatory Microenvironments

Abstract

Rheumatoid arthritis (RA) is sustained by a pathogenic circuit involving oxidative stress, synovial inflammation, and fibroblast-like synoviocyte (FLS) hyperactivation. Therapeutic strategies that simultaneously modulate these interconnected processes remain limited. Here, we report a single-component supramolecular hydrogel for local RA therapy based on a rationally designed small-molecule hydrogelator, Naproxen-Thioketal-Phe-Phe-Met(O) (NTF). NTF integrates an antiinflammatory drug moiety, a reactive oxygen species (ROS)-labile thioketal linker, and a self-assembling peptide motif, enabling spontaneous formation of an injectable nanofibrous hydrogel under physiological conditions. The resulting hydrogel exhibited ROS-responsive disassembly, sustained naproxen release under oxidative conditions, and marked radicalscavenging activity. In vitro, NTF inhibited the proliferation, migration, and invasion of rheumatoid arthritis-derived FLS, while also reducing intracellular ROS levels in activated macrophages. In a collagen-induced arthritis rat model, intraarticular administration of Gel NTF markedly alleviated joint swelling and arthritis severity, and reduced synovial inflammation and cartilage damage. Histological and immunohistochemical analyses further revealed reduced synovial hyperplasia, pannus formation, and TNF-α expression after treatment. These findings identify NTF as an intrinsically therapeutic hydrogelator that couples redox-responsive drug release with suppression of pathogenic synoviocyte behavior, and suggest a local strategy for interrupting the inflammatory microenvironment that drives RA progression.