Hyaluronic acid-anchored nanoparticles co-delivering emodin and siRNA confers protection against rheumatoid arthritis via macrophage polarization

Macrophages are key effector cells in the pathogenesis of rheumatoid arthritis (RA), and the pro-inflammatory M1 phenotype accelerates the release of cytokines and exacerbates joint inflammation. In this study, a modified Fe-based metal-organic framework (Fe-MOF) was designed for RA treatment by co-delivering emodin (EM) and small interfering RNA of Kelch-like ECH-associated protein 1 (siKEAP1). To target inflammatory lesions, hyaluronic acid (HA) was encapsulated on the surface of nanoparticles, thereby specifically binding to CD44 receptor overexpressed on M1 macrophage membranes. From the characterization, the synthesized EM/siKEAP1@Fe-MOF@HA exhibited a stable physicochemical profile and pH-responsive property. As expected, EM/siKEAP1@Fe-MOF@HA could effectively target macrophages and promote internalization through clathrin-mediated endocytosis. Both in vitro and in vivo experiments confirmed that the internalized nanoparticles reduced the levels of inflammatory factors and reactive oxygen species and promoted M2 macrophage polarization by releasing EM and downregulating KEAP1. EM/siKEAP1@Fe-MOF@HA can also alleviate the pathological features of RA mice. More importantly, EM/siKEAP1@Fe-MOF@HA maintained an optimistic biosafety profile, avoiding liver and kidney toxicity and damage to major organs. Overall, this nano-delivery system reduced the pathological and inflammatory responses of RA by targeting macrophages and mediating their polarization, and thus could serve as a safe and effective strategy in the treatment of RA.