Journal of nanobiotechnology · 2025
NaHS@Cy5@MS@SP nanoparticles improve rheumatoid arthritis by inactivating the Hedgehog signaling pathway through sustained and targeted release of H2S into the synovium.
СтатьяНазвание и аннотация: Перевод в очереди
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Zhu Xue-Xue, Xu An-Jing, Cai Wei-Wei, Han Zhi-Jun, Zhang Shi-Jie, Hou Bao, Wen Yuan-Yuan, Cao Xing-Yu, Li Hao-Dong, Du Yue-Qing, Zhuang You-Yi, Wang Jing, Hu Xiao-Ran, Bai Xin-Ran, Su Jia-Bao, Zhang Ao-Yuan, Lu Qing-Bo, Gu Ye, Qiu Li-Ying, Pan Lin, Sun Hai-Jian
Аннотация
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 AUCinf 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.
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 AUCinf 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.