Expanding Structural Space for Immunomodulatory Nucleic Acid Nanoparticles via Spatial Arrangement of Their Therapeutic Moieties

Abstract

Different therapeutic nucleic acids (TNAs) can be unified in a single structure by their elongation with short oligonucleotides designed to self-assemble into nucleic acid nanoparticles (NANPs). With this approach, therapeutic cocktails with precisely controlled composition and stoichiometry of active ingredients can be delivered to the same diseased cells for enhancing pharmaceutical action. In this study, an additional nanotechnology-based therapeutic option that enlists a biocompatible NANP-encoded platform for their controlled patient-specific immunorecognition is explored. For this, a set of representative functional NANPs is extensively characterized in vitro, ex vivo, and in vivo and then further analyzed for immunostimulation of human peripheral blood mononuclear cells freshly collected from healthy donor volunteers. The results of the study present the advancement of the current TNA approach toward personalized medicine and offer a new strategy to potentially address top public health challenges related to drug overdose and safety through the biodegradable nature of the functional platform with immunostimulatory regulation.

Therapeutic immunomodulation by rationally designed nucleic acids and nucleic acid nanoparticles

“…The response for some orientations of TNAs was stronger than for others. This data indicates that the cytosolic sensor, RIG-I, can distinguish between non-functional and functional NANPs and the extent of functionalization (94). Functional group delivery can be further controlled through the intracellular reassociation of RNA/DNA hybrid NANPs.…”

“…The response for some orientations of TNAs was stronger than for others. This data indicates that the cytosolic sensor, RIG-I, can distinguish between non-functional and functional NANPs and the extent of functionalization ( 94 ).…”

Break to Build: Isothermal Assembly of Nucleic Acid Nanoparticles (NANPs) via Enzymatic Degradation

“…We examined the immunostimulatory properties of our assemblies in reporter cell lines that express TLR7 (Toll-like receptor 7) or RIG-I (retinoic acid-inducible gene I). TLR7 is an endosomal receptor sensing ssRNAs and short dsRNAs in NANP structures, while RIG-I is a cytosolic receptor that recognizes RNA NANPs with triphosphate on the 5′ ends. ,− Naturally, cytokine production results from signaling pathways triggered through either PRR. Stimulation of TLR7 and RIG-I in engineered reporter cell lines activates expression and secretion of SEAP (secreted embryonic alkaline phosphatase) and luciferase, respectively (Figure e,f).…”

Nanoscale metal-organic frameworks for the delivery of nucleic acids to cancer cells

“…Future work will be required to explore nanoMOF's potential to deliver larger TNAs and nucleic acid complexes in conjunction with other anticancer therapeutics into cells. There is also potential to integrate these versatile nanoMOFs into higher ordered three-dimensional structures by using programmable nucleic acids ( Chandler et al, 2021 ; Chandler et al, 2022 ).…”