A Unique Gene-Silencing Approach, Using an Intelligent RNA Expression Device (iRed), Results in Minimal Immune Stimulation When Given by Local Intrapleural Injection in Malignant Pleural Mesothelioma

Abstract

Background: We have recently introduced an intelligent RNA expression device (iRed), comprising the minimum essential components needed to transcribe short hairpin RNA (shRNA) in cells. Use of iRed efficiently produced shRNA molecules after transfection into cells and alleviated the innate immune stimulation following intravenous injection. Methods: To study the usefulness of iRed for local injection, the engineered iRed encoding luciferase shRNA (Luc iRed), complexed with cationic liposomes (Luc iRed/liposome-complexes), was intrapleurally injected into an orthotopic mesothelioma mouse model. Results: Luc iRed/liposome-complexes markedly suppressed the expression of a luciferase marker gene in pleurally disseminated mesothelioma cells. The suppressive efficiency was correlated with the expression level of shRNA within the mesothelioma cells. In addition, intrapleural injection of iRed/liposome-complexes did not induce IL-6 production in the pleural space and consequently in the blood compartment, although plasmid DNA (pDNA) or dsDNA (the natural construct for iRed) in the formulation did. Conclusion: Local delivery of iRed could augment the in vivo gene silencing effect without eliciting pronounced innate immune stimulation. Our results might hold promise for widespread utilization of iRed as an RNAi-based therapeutic for intracelial malignant cancers.

Special Issue “Recent Advances in Precision Nanomedicine for Cancer”

“…This application might be considered as a novel precision medicine-based approach to overcome some obstacles frequently raised during the development of natural product drugs [ 2 ]. Ando H. et al [ 3 ] propose the use of an intelligent RNA expression device (iRed), complexed to cationic liposomes, to augment an in vivo gene silencing effect without eliciting marked innate immune stimulation. The results obtained by the authors demonstrate that iRed-liposome complexes successfully induce efficient gene silencing against pleurally disseminated mesothelioma tumors, while alleviating the innate immune stimulatory effect, paving the way for their widespread utilization as precision nanomedicines for intracelial malignant cancers [ 3 ].…”

“…Ando H. et al [ 3 ] propose the use of an intelligent RNA expression device (iRed), complexed to cationic liposomes, to augment an in vivo gene silencing effect without eliciting marked innate immune stimulation. The results obtained by the authors demonstrate that iRed-liposome complexes successfully induce efficient gene silencing against pleurally disseminated mesothelioma tumors, while alleviating the innate immune stimulatory effect, paving the way for their widespread utilization as precision nanomedicines for intracelial malignant cancers [ 3 ]. Samec N. et al [ 4 ] present an overview of the use of nanoparticles as tools for the diagnosis and treatment of grade IV glioblastoma, an aggressive brain tumor, whose current therapies are ineffective and patient survival rates and prognosis are very poor.…”