Immunostimulation
of Fibrous Nucleic Acid Nanoparticles
Can be Modulated through Aptamer-Based Functional Moieties: Unveiling
the Structure–Activity Relationship and Mechanistic Insights
posted on 2024-02-12, 10:03authored byLaura
P. Rebolledo, Weina Ke, Edward Cedrone, Jian Wang, Krishna Majithia, M. Brittany Johnson, Nikolay V. Dokholyan, Marina A. Dobrovolskaia, Kirill A. Afonin
Fibrous nanomaterials
containing silica, titanium oxide, and carbon
nanotubes are notoriously known for their undesirable inflammatory
responses and associated toxicities that have been extensively studied
in the environmental and occupational toxicology fields. Biopersistance
and inflammation of “hard” nanofibers prevent their
broader biomedical applications. To utilize the structural benefits
of fibrous nanomaterials for functionalization with moieties of therapeutic
significance while preventing undesirable immune responses, researchers
employ natural biopolymersRNA and DNAto design “soft”
and biodegradable nanomaterials with controlled immunorecognition.
Nucleic acid nanofibers have been shown to be safe and efficacious
in applications that do not require their delivery into the cells
such as the regulation of blood coagulation. Previous studies demonstrated
that unlike traditional therapeutic nucleic acids (e.g., CpG DNA oligonucleotides)
nucleic acid nanoparticles (NANPs), when used without a carrier, are
not internalized by the immune cells and, as such, do not induce undesirable
cytokine responses. In contrast, intracellular delivery of NANPs results
in cytokine responses that are dependent on the physicochemical properties
of these nanomaterials. However, the structure–activity relationship
of innate immune responses to intracellularly delivered fibrous NANPs
is poorly understood. Herein, we employ the intracellular delivery
of model RNA/DNA nanofibers functionalized with G-quadruplex-based
DNA aptamers to investigate how their structural properties influence
cytokine responses. We demonstrate that nanofibers’ scaffolds
delivered to the immune cells using lipofectamine induce interferon
response via the cGAS-STING signaling pathway activation and that
DNA aptamers incorporation shields the fibers from recognition by
cGAS and results in a lower interferon response. This structure–activity
relationship study expands the current knowledge base to inform future
practical applications of intracellularly delivered NANPs as vaccine
adjuvants and immunotherapies.