Injectable Hyaluronic Acid-Functionalized Nanocomposite Hydrogel for Targeted Rheumatoid Arthritis Therapy via Concurrent ROS Attenuation and Macrophage Repolarization.

BACKGROUND

The clinical treatment of rheumatoid arthritis (RA), a chronic systematic autoimmune disease marked by persistent synovial inflammation and irreversible joint damage, remains substantially challenging due to the limitations of current therapies including insufficient targeting, short intra-articular retention and off-target adverse effects. Therefore, developing an injectable, long-acting and targeted therapeutic hydrogel platform is urgently needed for precise and efficient RA treatment.

METHODS

We developed an injectable long-acting nanocomposite hydrogel platform (HA-BR nano-GEL@CLT) which integrated hyaluronic acid (HA)-polyethylene glycol (PEG) co-polymeric matrix encapsulating HA-bilirubin nanoparticles (HA-BR NPs) and celastrol (CLT). The hydrogel was characterized and its in vitro biocompatibility, antioxidant, anti-inflammatory, and macrophage polarization effects were evaluated. In vivo therapeutic efficacy and biosafety were assessed in adjuvant-induced arthritis (AIA) rats.

RESULTS

The average particle size of fabricated HA-BR NPs@CLT was 118.5 nm and the gel formulation underwent a rapid sol‑to‑gel phase transition within 200 seconds. HA-BR nano-GEL@CLT exhibited strong biomimetic lubrication, anti-inflammatory and antioxidant capacities, and could effectively modulate the polarization of macrophages in vitro, with the result that the M1/M2 ratio in HA-BR nano-GEL@CLT group was only 0.19-fold that of model group. The hydrogel also provided long-term intra-articular retention up to 21 days in AIA rats. It significantly alleviated paw swelling, inhibited bone erosion, modulated the levels of inflammatory cytokines, whereas the expressions of IL-6 and TNF-α were reduced by 27% and 43%, and the expression of IL-10 was increased by 47%, compared to HA GEL@CLT group. Besides, HA-BR nano-GEL@CLT also alleviated oxidative damage, regulated macrophage polarization and reduced systemic toxicity of CLT in vivo.

CONCLUSION

This injectable nanocomposite hydrogel platform offers an efficient and promising approach to suppress RA progression via ROS attenuation and macrophage repolarization.