Combined delivery of HMGB-1 box A peptide and S1PLyase siRNA in animal models of acute lung injury.

The combinational therapy with S1Plyase siRNA (siS1PLyase) and recombinant high mobility group box-1 box A peptide (HMGB1A) may have a synergistic effect for the treatment of acute lung injury (ALI). For efficient delivery, the R3V6 peptides were used as a carrier. The ternary complex of siS1PLyase, HMGB1A, and R3V6 was produced by charge interaction. The siS1PLyase/HMGB1A/R3V6 ternary complex delivered siRNA into the LA-4 lung epithelial cells more efficiently than polyethylenimine (PEI) and Lipofectamine. Furthermore, the ternary complex was non-toxic. The siS1PLyase/HMGB1A/R3V6 complex reduced the levels of IL-6 and TNF-α more efficiently than HMGB1A only or siS1PLyase/R3V6 complex in the LPS activated macrophage cells. In vivo administration of the siS1PLyase/HMGB1A/R3V6 complex reduced the S1PLyase level efficiently in an LPS-induced ALI model. Furthermore, the complex reduced the inflammatory response and apoptosis in the ALI model. In conclusion, siS1PLyase and HMGB1A have a synergistic therapeutic effect for the treatment of ALI. Furthermore, R3V6 is an efficient carrier for combined delivery of siS1PLyase and HMGB1A.