Restoring macrophage iron homeostasis by natural carrier-free nanoplatform for the therapy of rheumatoid arthritis syndromes.

Focal iron overload frequently induce macrophage polarization towards pro-inflammatory subtypes, leading to joint inflammation, cartilage damage and anemia in rheumatoid arthritis (RA) patients. Faced with the complex and lingering pathogenesis of RA, there is an urgent need to develop safe and effective strategies. The active ingredients from traditional herbal pair, namely roburic acid (RBA) and tetramethylpyrazine (TMP), have potential values in the anti-inflammatory and antiplatelet aggregation biological activities. However, their poor water solubility and low bioavailability limit their strong clinical application. To break this bottleneck, we developed a carrier-free nanomedicine (RTNs) through the self-assembly of RBA and TMP for RA syndromes treatment. RTNs formed through electrostatic interactions and hydrogen bonding exhibited strong inflammatory joint accumulation and long-term circulation in adjuvant-induced arthritis (AIA) rodents model. At the same time, RTNs outperformed the same doses of free RBA and TMP in the terms of good therapeutic effects in inhibiting joint inflammation, improving cartilage destruction, and alleviating RA secondary anemia. What's more, RTNs demonstrated good safety and biocompatibility. Finally, with the help of single-cell sequencing analysis and in vitro and in vivo research, we elucidated that RTNs restored macrophage iron homeostasis via facilitating ferroportin (FPN) level, and ultimately regulated macrophage function to treat RA syndromes. Overall, this study provides new insights into the application of carrier-free self-assembly of natural product medicines in the efficient and safe therapy of RA involving complex syndromes.