Smart-Responsive Nucleic Acid Nanoparticles (NANPs) with the Potential to Modulate Immune Behavior

Abstract

Nucleic acids are programmable and biocompatible polymers that have beneficial uses in nanotechnology with broad applications in biosensing and therapeutics. In some cases, however, the development of the latter has been impeded by the unknown immunostimulatory properties of nucleic acid-based materials, as well as a lack of functional dynamicity due to stagnant structural design. Recent research advancements have explored these obstacles in tandem via the assembly of three-dimensional, planar, and fibrous cognate nucleic acid-based nanoparticles, called NANPs, for the conditional activation of embedded and otherwise quiescent functions. Furthermore, a library of the most representative NANPs was extensively analyzed in human peripheral blood mononuclear cells (PBMCs), and the links between the programmable architectural and physicochemical parameters of NANPs and their immunomodulatory properties have been established. This overview will cover the recent development of design principles that allow for fine-tuning of both the physicochemical and immunostimulatory properties of dynamic NANPs and discuss the potential impacts of these novel strategies.

Nucleic Acid Nanoparticles at a Crossroads of Vaccines and Immunotherapies

“…More importantly, NANPs technology is flexible and allows adding functionalities and swap individual nucleotides without altering the entire nanoparticle assembly [70]. As such, NANPs can be designed to form non-functional scaffolds, which are typically made of DNA, RNA or DNA-RNA hybrid oligonucleotides not-specific to any particular target gene, use these scaffolds to simultaneously deliver multiple different gene-specific therapeutic oligonucleotides (e.g., siRNAs or miRNAs) and create more sophisticated materials with conditionally activatable split functionalities [46,48,53,54,[65][66][67][68][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85]. A co-delivery of individual non-functional scaffolds is required for applications involving NANPs with split functionalities and have been demonstrated in biological systems both in vitro and in vivo [53,73,74,77,82].…”

“…There is also an increasing trend in considering the NANP scaffolds for the controlled immunomodulation, wherein control is provided by several means including but not limited to modifications in the nanoparticle physicochemical properties (e.g., composition, size, shape, sequence complementarity, connectivity), delivery vehicle, dose and route of administration [76,81,82,86,87].…”

“…NANPs split functionality can be created when two individually non-functional NANPs are co-delivered into the same cell where they re-associate to create a fully functional NANP [76,77,123]. This modality provides both off and on switches to NANP-mediated biological responses.…”

“…When individual NANPs get off-target, the lack of their functionality at the individual level would prevent undesirable side effects. Afonin et al proposed an interesting concept in which an individual functional NANP is administered as a single therapeutic entity, then another NANP neutralizing the effect of the functional NANP is administered to quench the biological response and thereby avoid avert response [76,77,123]. This controlled "off" property is very attractive in immunotherapy, as it may provide control over the activated immune cells to avoid auto-immunity.…”

“…NANPs' molecular weight and structure are different from those of the traditional TNA. While NANPs versatility and strategies for design of functional NANPs have been studied extensively [46][47][48][49][50][51][52][53]55,57,[65][66][67][68][70][71][72][73][74][76][77][78][79][80][81]83,86,91,92,[95][96][97][98]100,102,103,121,[129][130][131][132][133][134][135][136][137][138][139][140][141]…”