Lipid-derived nanoparticles for immunostimulatory RNA adjuvant delivery
Name
Anderson_Lipid-derived.pdf
Size
2.12 MB
Format
Adobe PDF
Checksum (MD5)
9aa203fc9ebcc403b9befc1ba7ea16b9
Author(s)
Nguyen, David N.
Mahon, Kerry P.
Chikh, Ghania
Kim, Phillip
Chung, Hattie
Vicari, Alain P.
Love, Kevin T.
Goldberg, Michael Solomon
Chen, Steve
Krieg, Arthur M.
Date Issued
March 2012
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Nguyen, D. N., K. P. Mahon, G. Chikh, P. Kim, H. Chung, A. P. Vicari, K. T. Love, et al. “Lipid-Derived Nanoparticles for Immunostimulatory RNA Adjuvant Delivery.” Proceedings of the National Academy of Sciences 109, no. 14 (March 15, 2012): E797–E803.
Version
Final published version
Abstract
The specific activation of Toll-like receptors (TLRs) has potential utility for a variety of therapeutic indications including antiviral immunotherapy and as vaccine adjuvants. TLR7 and TLR 8 may be activated by their native ligands, single-stranded RNA, or by small molecules of the imidazoquinoline family. However the use of TLR7/8 agonists for in vivo therapy is limited by instability, in the case of RNA, or systemic biodistribution and toxicity in the case of small molecule agonists. We hypothesized that unique lipid-like materials, termed “lipidoids,” could be designed to efficiently deliver immunostimulatory RNA (isRNA) to TLR-expressing cells to drive innate and adaptive immune responses. A library of lipidoids was synthesized and screened for the ability to induce type I IFN activation in human peripheral blood mononuclear cells when combined with isRNA oligonucleotides. Effective lipidoid-isRNA nanoparticles, when tested in mice, stimulated strong IFN-α responses following subcutaneous injection, had robust antiviral activity that suppressed influenza virus replication, and enhanced antiovalbumin humoral and cell-mediated responses when used as a vaccine adjuvant. Further, we demonstrate that whereas all immunological activity was MyD88-dependent, certain materials were found to engage both TLR7-dependent and TLR7-independent activity in the mouse suggestive of cell-specific delivery. These lipidoid formulations, which are materials designed specifically for delivery of isRNA to Toll-like receptors, were superior to the commonly used N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate–RNA delivery system and may provide new tools for the manipulation of TLR responses in vitro and in vivo.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1073/pnas.1121423109
