Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery.
Nanoparticles are used for delivering therapeutics into cells. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell-specific internalization, excretion, toxicity and efficacy. A variety of materials have been explored for delivering small interfering RNAs (siRNAs)--a therapeutic agent that suppresses the expression of targeted genes. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, a lack of tissue specificity and potential toxicity. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer-targeting ligands (such as peptides and folate) on the nanoparticle surface can be controlled precisely. We show that at least three folate molecules per nanoparticle are required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t(1/2) ≈ 24.2 min) than the parent siRNA (t(1/2) ≈ 6 min).
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Hyukjin
H
Lee
Abigail K R
AK
Lytton-Jean
Yi
Y
Chen
Kevin T
KT
Love
Angela I
AI
Park
Emmanouil D
ED
Karagiannis
Alfica
A
Sehgal
William
W
Querbes
Christopher S
CS
Zurenko
Muthusamy
M
Jayaraman
Chang G
CG
Peng
Klaus
K
Charisse
Anna
A
Borodovsky
Muthiah
M
Manoharan
Jessica S
JS
Donahoe
Jessica
J
Truelove
Matthias
M
Nahrendorf
Robert
R
Langer
Daniel G
DG
Anderson
D000818:Animals; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005492:Folic Acid / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology
D034741:RNA, Small Interfering; D004247:DNA; D005492:Folic Acid