RAGE-targeted delivery of anti-microRNA-92a antagomir for the treatment of acute lung injury

Abstract

Acute lung injury (ALI) is an inflammatory lung disease. Gene therapy for ALI has been investigated to reduce lung inflammation. The receptor for advanced glycation end- products (RAGE) is induced and plays an important role in inflammation response in ALI. The RP1 peptide was previously reported to bind to RAGE. In this study, the R3V6 peptide linked with the RP1 peptide (RP1R3V6) was synthesized and evaluated as a gene carrier into the lungs of ALI animal models. Since microRNA-92a (miR-92a) is known as a mediator for inflammation reaction, inhibition of miR-92a may reduce lung inflammation in ALI animal models. Therefore, antagomir miR-92a (AMO92a) was delivered into the lungs using RP1R3V6 as a carrier. Because RP1 may interact with RAGE, RP1R3V6 might increase the AMO92a delivery efficiency to RAGE-positive cells. In a gel retardation assay, AMO92a and RP1R3V6 formed stable complexes. In vitro cytotoxicity test showed that the AMO92a/RP1R3V6 complex was less toxic, compared with AMO92a/R3V6 or AMO92a/polyethylenimine (25 kDa, PEI25K). In vitro study showed that AMO92a delivered with RP1R3V6 efficiently reduced the miR-92a level. In vivo administration of the AMO92a/RP1R3V6 complex into an LPS-induced ALI model reduced the miR-92a level efficiently. Furthermore, the AMO92a/RP1R3V6 complex reduced the pro-inflammatory cytokine levels (TNF-α/IL-6/IL-1β) more efficiently than the AMO92a/R3V6 or AMO92a/PEI25K. In conclusion, the RP1R3V6 is an efficient carrier of AMO92a into the lungs and may be useful for the treatment of ALI.