Innate Immunity of Framework Nucleic Acids.
ConspectusNucleic acid nanotechnology has fundamentally transcended the classic paradigm of DNA and RNA as passive carriers of genetic blueprints, which enables the rational design and construction of precise nanostructures with defined shapes, dynamics, and functions. This programmability has revolutionized approaches in biomedicine, facilitating breakthroughs in high-resolution molecular diagnostics, spatially and temporally controlled drug delivery, and the creation of synthetic cellular machinery. However, a central challenge for clinical translation is the inherent immunogenicity of nucleic acid materials. Introducing exogenous DNA or RNA nanostructures risks triggering potent innate immune responses, which can lead to rapid clearance, diminished therapeutic efficacy, inflammation, and toxicity. Rather than pursuing universal immunosuppression, researchers are beginning to rationally exploit defined immunostimulatory pathways, which allows for the strategic incorporation of immune-modulatory cues for vaccine development, immunotherapies, and targeted adjuvant systems.In this Account, we review our efforts to develop framework nucleic acids (FNAs) as a platform with modulable innate immunostimulation for biomedical applications in live cells and in vivo. We briefly summarize structural principles of nucleic acid immune recognition mediated by receptors such as toll-like receptors (TLRs) and cyclic GMP-AMP synthase (cGAS). We highlight that such immune recognition is dictated not merely by the abundance of nucleic acids but by key structural parameters, including size, shape, compactness, and the spatial organization of stimulatory nucleic acid motifs. We illustrate strategies to either enhance or suppress immunostimulation through controlled biodistribution, multivalent ligand display, and dynamic structural reconfiguration. These approaches enable tailored applications such as the development of nanovaccines and cancer immunotherapy, or conversely, anti-inflammatory and antioxidant therapies. Looking forward, we envision FNAs as intelligent tools for precision immunomodulation, bridging nanoscale design with immunological outcomes to advance personalized medicine.