Drug delivery-mediated control of RNA immunostimulation.
RNA interference (RNAi) has generated significant interest as a strategy to suppress viral infection, but in some cases antiviral activity of unmodified short-interfering RNA (siRNA) has been attributed to activation of innate immune responses. We hypothesized that immunostimulation by unmodified siRNA could mediate both RNAi as well as innate immune stimulation depending on the mode of drug delivery. We investigated the potential of immunostimulatory RNAs (isRNAs) to suppress influenza A virus in vivo in the mouse lung. Lipidoid 98N12-5(1) formulated with unmodified siRNA targeting the influenza nucleoprotein gene exhibited antiviral activity. Formulations were optimized to increase antiviral activity, but the antiviral activity of lipidoid-delivered siRNA did not depend on sequence homology to the influenza genome as siRNA directed against unrelated targets also suppressed influenza replication in vivo. This activity was primarily attributed to enhancement of innate immune stimulation by lipidoid-mediated delivery, which indicates increased toll-like receptor (TLR) activation by siRNA. Certain chemical modifications to the siRNA backbone, which block TLR7/8 activation but retain in vitro RNAi activity, prevented siRNA-mediated antiviral activity despite enhanced lipidoid-mediated delivery. Here, we demonstrate that innate immune activation caused by unmodified siRNA can have therapeutically relevant effects, and that these non-RNAi effects can be controlled through chemical modifications and drug delivery.
Nguyen
David N
DN
Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts 02142, USA.
Chen
Steve C-Y
SC
Lu
James
J
Goldberg
Michael
M
Kim
Phillip
P
Sprague
Andrew
A
Novobrantseva
Tatiana
T
Sherman
Jennifer
J
Shulga-Morskaya
Svetlana
S
de Fougerolles
Antonin
A
Chen
Jianzhu
J
Langer
Robert
R
Anderson
Daniel G
DG
D000818:Animals; D000998:Antiviral Agents / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D007114:Immunization / Q000379:methods*; D009980:Influenza A virus / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D053758:Nanoparticles; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology; D034622:RNA Interference / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
D000998:Antiviral Agents; D034741:RNA, Small Interfering; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors