Therapeutic Nucleic Acid-based Nanoparticles with Controlled Immunomodulatory Properties Kirill A. Afonin1, Marina A. Dobrovolskaia2, 1University of North Carolina at Charlotte, USA; 6NCL Frederick National Laboratory for Cancer Research, FNLCR, USA
Therapeutic nucleic acids have evolved as a promising platform for the detection and treatment of a wide range of diseases and maladies. In the past year, however, there have been several announcements that U.S. biotech companies have discontinued clinical development of therapeutic nucleic acids formulated using lipid-based carriers citing severe “cytokine storm” inflammatory reactions and limited efficacy among reasons for the discontinuation of such formulations. To address these barriers, more sophisticated formulations that employ rationally designed RNA molecules have been designed. The ability of RNA to assemble into discrete and uniform shapes make them a viable option for a number of biomedical applications and to become one of the next milestones in personalized medicines along with small molecule and protein-based pharmaceuticals. It is becoming apparent that interactions between RNA nanoassemblies and the immune system must be defined to permit the successful translation of this technology to the clinic. Therefore, to address fundamental questions regarding the immune recognition of these novel materials, we have designed the following study in which features such as size, shape, composition, and physicochemical properties of nucleic acid nanoparticles were related to their therapeutic activity in human cancer cells and activation of immune responses in human immune cells. We designed, assembled and characterized a series of RNA, DNA, and RNA/DNA hybrid nanoparticles and further surveyed the link between their size, composition, physical and chemical properties to the pro-inflammatory responses. The biomarkers of pro-inflammatory response were cytokines and type I interferons. This work is instrumental in bridging the rapidly narrowing gap between basic research on nucleic acid nanoparticles and advanced pharmaceuticals containing these novel materials.
Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM120487. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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