Nucleic acid nanotechnology is a rising star in medical applications including diagnostics and therapeutics due to the recent advances in nanotechnology and therapeutic nucleic acids (TNAs). The relatively straightforward approaches of bottom-up design and assembly of various functional nucleic acid nanoparticles (NANPs) offer advantages for diverse applications in medicine and biotechnology. The combination of several noncoding nucleic acids within NANPs provided simultaneous regulation of physiological processes. However, the novelty of this approach hindered the used of NANPs in clinical settings, as the full realization of NANPs’ potential demands the development of a safe, efficient, stable, biocompatible, tissue-specific, and non- immunogenic delivery system. It has been established that NANPs’ physicochemical properties including size, composition, and shape, determine their interactions with immune cells in the human body, enable recognition by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and mediate the subsequent cytokine response. Recent findings have provided increasing evidence that NANPs’ interactions with immune cells can be regulated through numerous independently programmable architectural parameters. For several decades, all efforts were directed to masking the immunogenic effect of nanomaterials used for drug delivery, only recently this challenge is being exploited to modulate the immune response through NANPs delivery. Therefore, understanding the pathway that regulates the recognition of NANPs by immune cells provides the rationale for developing therapeutic NANPs with tunable immune stimulation for various applications. In addition, currently in preclinical investigations it is focused on the immune recognition of NANPs aiming to enable the translation of these novel materials into clinical settings. Hence, defined immunomodulation by NANPs can be used for conditional stimulation of beneficial immunological responses or to support their immunoquiescent delivery.

 

Keywords: Nucleic acid nanoparticles (NANPs), Therapeutic nucleic acids (TNAs), Immunorecognition, Immunoreaction; Nanotechnology; Drug delivery