Mechanism for the endocytosis of spherical nucleic acid nanoparticle conjugates

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 19; pp. 7625 - 7630
• Main Authors: Choi, Chung Hang J., Hao, Liangliang, Narayan, Suguna P., Auyeung, Evelyn, Mirkin, Chad A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.05.2013; National Acad Sciences
• Subjects: Animals; B lymphocytes; Biological Sciences; Biological Transport; Cell Line; Cell lines; Cell membranes; Cells; DNA, Single-Stranded - chemistry; Endocytosis; Endothelial cells; Gene Transfer Techniques; Genetic Vectors; Humans; Imaging; Kinetics; Lipids; Membrane Microdomains - metabolism; Mice; Nanoparticles; Nanoparticles - chemistry; Nucleic acids; Nucleic Acids - pharmacokinetics; Oligonucleotides; Oligonucleotides - chemistry; Oligonucleotides - pharmacokinetics; Proteins; RNA Interference; T lymphocytes; Time Factors; Toxicity; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1305804110

Intracellular delivery of nucleic acids as gene regulation agents typically requires the use of cationic carriers or viral vectors, yet issues related to cellular toxicity or immune responses hamper their attractiveness as therapeutic candidates. The discovery that spherical nucleic acids (SNAs), polyanionic structures comprised of densely packed, highly oriented oligonucleotides covalently attached to the surface of nanoparticles, can effectively enter more than 50 different cell types presents a potential strategy for overcoming the limitations of conventional transfection agents. Unfortunately, little is known about the mechanism of endocytosis of SNAs, including the pathway of entry and specific proteins involved. Here, we demonstrate that the rapid cellular uptake kinetics and intracellular transport of SNAs stem from the arrangement of oligonucleotides into a 3D architecture, which supports their targeting of class A scavenger receptors and endocytosis via a lipid-raft–dependent, caveolae-mediated pathway. These results reinforce the notion that SNAs can serve as therapeutic payloads and targeting structures to engage biological pathways not readily accessible with linear oligonucleotides.