ROS-responsive Naproxen-peptide hydrogel (NTF) attenuates rheumatoid arthritis by modulating synoviocytes and inflammation

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, cartilage destruction, and bone erosion. A key driver is the hyperactivation of fibroblast-like synoviocytes (FLS), which proliferate excessively and contribute to the inflammatory microenvironment, often resistant to current therapies. Furthermore, oxidative stress plays a significant role in sustaining this pathogenic cycle. There is a critical need for therapeutic strategies that can simultaneously target FLS activity, inflammation, and oxidative stress to effectively interrupt RA progression.

Researchers developed a single-component supramolecular hydrogel, Naproxen-Thioketal-Phe-Phe-Met(O) (NTF), designed for local RA therapy. This hydrogelator integrates an anti-inflammatory drug (naproxen), an ROS-labile linker, and a self-assembling peptide motif. They evaluated its efficacy in vitro by assessing the proliferation, migration, and invasion of rheumatoid arthritis-derived FLS, and intracellular ROS levels in activated macrophages. In vivo, the team administered Gel NTF via intra-articular injection in a collagen-induced arthritis (CIA) rat model, monitoring joint swelling, arthritis severity, and histological markers of synovial inflammation and cartilage damage.

The NTF hydrogel demonstrated ROS-responsive disassembly, enabling sustained naproxen release under oxidative conditions, alongside marked radical-scavenging activity. In vitro, NTF significantly inhibited the proliferation, migration, and invasion of rheumatoid arthritis-derived FLS. It also reduced intracellular ROS levels in activated macrophages. In the collagen-induced arthritis rat model, intra-articular administration of Gel NTF led to a marked alleviation of joint swelling and arthritis severity. Histological and immunohistochemical analyses further revealed:

Reduced synovial inflammation and cartilage damage, alongside decreased synovial hyperplasia, pannus formation, and TNF-α expression after treatment. These findings highlight NTF's ability to couple redox-responsive drug release with suppression of pathogenic synoviocyte behavior.