An enhanced RRM2 siRNA delivery to rheumatoid arthritis fibroblast-like synoviocytes through a liposome-protamine-DNA-siRNA complex with cell permeable peptides

摘要

Rheumatoid arthritis (RA) is considered to be a systemic autoimmune disease that induces systemic complications and progressive disability. It affects a large number of people. RA fibroblast-like synoviocytes (RA-FLS) promote the progression of RA through the secretion of proinflammatory cytokines and increasing invasiveness into the extracellular matrix. Therefore, targeting RA-FLS represents a potential approach for the treatment of RA. Ribonucleotide reductase M2 (RRM2), a critical protein for DNA synthesis and repair, may promote the proliferation of cells and inhibit cellular apoptosis. In previous studies it has been confirmed that the suppression of RRM2 markedly suppressed the proliferation of liver cancer cells. In the present study, a cell permeable peptide-conjugated liposome-polycation-DNA (LPD) complex loaded with RRM2 small interfering RNA (siRNA) (CCP-LPDR) was developed, aiming to increase the levels of apoptosis and inhibit the proliferation of RA-FLS. CCP-LPDR is a small-sized molecule (~130 nm) with high encapsulation efficiency of siRNA (>90%) and high stability. Furthermore, it was verified that CCP-LPDR markedly suppressed RRM2 gene and protein expression by ~80%. Notably, CCP-LPDR efficiently targeted RA-FLS, resulting in a marked decrease in the proliferation and increase in the level of apoptosis in RA-FLS. In addition, the levels of proinflammatory cytokines tumor necrosis factor-α and interleukin-6 were markedly decreased in RA-FLS following CCP-LPDR treatment. Therefore, CCP-LPDR may efficiently deliver RRM2 to RA-FLS and represent a potential treatment for RA.