Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes

TLDR

RNA interference holds therapeutic promise, but delivery of nucleic acids across cell membranes remains a major obstacle. The authors optimized electroporation to load siRNA into plasma exosomes, which were then used as a gene delivery vector to transport the RNA into blood cells. The exosomes successfully delivered siRNA to monocytes and lymphocytes, selectively silencing MAPK1 and demonstrating that human exosomes can serve as a gene delivery vector for therapeutic siRNAs.

Abstract

Despite the promise of RNA interference (RNAi) and its potential, e.g. for use in cancer therapy, several technical obstacles must first be overcome. The major hurdle of RNAi-based therapeutics is to deliver nucleic acids across the cell's plasma membrane. This study demonstrates that exosome vesicles derived from humans can deliver short interfering RNA (siRNA) to human mononuclear blood cells. Exosomes are nano-sized vesicles of endocytic origin that are involved in cell-to-cell communication, i.e. antigen presentation, tolerance development and shuttle RNA (mainly mRNA and microRNA). Having tested different strategies, an optimized method (electroporation) was used to introduce siRNA into human exosomes of various origins. Plasma exosomes (exosomes from peripheral blood) were used as gene delivery vector (GDV) to transport exogenous siRNA to human blood cells. The vesicles effectively delivered the administered siRNA into monocytes and lymphocytes, causing selective gene silencing of mitogen-activated protein kinase 1. These data suggest that human exosomes can be used as a GDV to provide cells with heterologous nucleic acids such as therapeutic siRNAs.