期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：13
页码：3892-3897
DOI：10.1073/pnas.1502850112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWe show that by organizing immunomodulatory nucleic acids into spherical nucleic acid (SNA) form, significant increases in activity are observed. Treatment of mice with cancer using immunostimulatory SNAs and nonalcoholic steatohepatitis (NASH) using immunoregulatory SNAs leads to improved disease outcomes vs. their unstructured counterparts. These improvements derive from several key SNA properties, including rapid cellular uptake, endosomal delivery, and multivalent binding. Overall, this work underscores the importance of the spatial orientation and presentation of oligonucleotides in the design of novel immunomodulators. Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clinical progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.
