NaHS@Cy5@MS@SP nanoparticles improve rheumatoid arthritis by inactivating the Hedgehog signaling pathway through sustained and targeted release of H2S into the synovium.

Background: Aberrant proliferation and inflammation of fibroblast-like synoviocytes (FLSs) significantly contribute to the pathogenesis of rheumatoid arthritis (RA). Deficiency of hydrogen sulfide (H₂S) is a driving force for the development of RA, and the short half-life of the H₂S-releasing donor sodium hydrosulfide (NaHS) limits its clinical application in RA therapy. Designing a targeted delivery system with slow-release properties for FLSs could offer novel strategies for treating RA.

Methods: Herein, we designed a strategy to achieve slow release of H₂S targeted to the synovium, which was accomplished by synthesizing NaHS-CY5@mesoporous silic@LNP targeted peptide Dil (NaHS@Cy5@MS@SP) nanoparticles.

Results: Our results demonstrated that NaHS@Cy5@MS@SP effectively targets FLSs, upregulates H₂S and its-producing enzyme cystathionine-γ-lyase (CSE) in the joints of arthritic mice. Overexpression of CSE inhibited the proliferation, migration, and inflammation of FLSs upon lipopolysaccharide (LPS) exposure, effects that were mimicked by NaHS@Cy5@MS@SP. In vivo studies showed that NaHS@Cy5@MS@SP achieved a threefold higher AUC_inf than that of free NaHS, significantly improving the bioavailability of NaHS. Further, NaHS@Cy5@MS@SP inhibited synovial hyperplasia and reduced bone and cartilage erosion in the DBA/1J mouse model of collagen-induced arthritis (CIA), which was superior to NaHS. RNA sequencing and molecular studies validated that NaHS@Cy5@MS@SP inactivated the Hedgehog signaling pathway in FLSs, as evidenced by reductions in the protein expression of SHH, SMO, GLI1 and phosphorylated p38/MAPK.

Conclusion: This study highlights NaHS@Cy5@MS@SP as a promising strategy for the controlled and targeted delivery of H₂S to synoviocytes, offering potential for RA management.