Multifunctional Prussian blue nanoparticles loading with Xuetongsu for efficient rheumatoid arthritis therapy through targeting inflammatory macrophages and osteoclasts

Abnormal activation of macrophages and osteoclasts (OCs) contributes significantly to rheumatoid arthritis (RA) development by secretion of numerous inflammatory factors. Notably, these cells exhibit significant upregulation of folate receptor proteins on their surfaces. Unfortunately, there is a current lack of safe and effective therapeutic drugs for RA. Xuetongsu (XTS), a triterpenoid compound extracted from <i>Kadsura heteroclita</i> Roxb Craib, has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes (RAFLS). However, its clinical application is hampered by poor targeting and short half-life. To address these drawbacks, we previously developed a nano-drug system named HRPS nanoparticles (NPs), which effectively targets RAFLS and inhibits synovial hyperplasia. However, this system overlooked the essential role of OCs in RA-related bone destruction. Therefore, we designed a novel folate-modified biomimetic Prussian blue (PB)-XTS NP (FMPX NP) for the selective delivery of XTS into inflammatory macrophages and OCs. The NP exhibits an excellent photothermal effect when assisted by laser irradiation, facilitating targeted release of XTS within inflammatory macrophages and OCs. The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs. <i>In vivo</i> experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times, decreased hind foot swelling from 12.10 ± 0.49 mm to 8.24 ± 0.09 mm in the model group, and prevented bone damage. In conclusion, this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA. FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy, providing new insights for targeted drug therapies in clinical RA treatment.