Nucleic acid nanomaterials: Mechanisms and strategies for regulating innate immune activation

Nucleic acid nanomaterials (NA-NMat) are rapidly emerging as pivotal tools in precision medicine and therapeutic interventions, with their immunomodulatory roles attracting frontier research focuses. As key triggers of innate immunity, nucleic acids orchestrate complex immune regulations through their distinct structural motifs and sequence-dependent molecular recognition. Elucidating the molecular mechanisms by which nucleic acids activate the innate immune system not only helps to reveal their central roles in immune regulation, but also lays the theoretical foundation for developing innovative nucleic acid-based therapeutic strategies. In this review, we systematically summarize current knowledge regarding the activation pathways, sequence specificity, and conformational effects of nucleic acids including the primary, secondary, tertiary, and artificially designed structures of DNA and RNA in innate immunity. We further review recent advancements in utilizing NA-NMat integrated with oligonucleotides, proteins, and small molecules to co-regulate innate immunity. To conclude, we critically evaluate current challenges in the field and propose future directions for the development of nucleic acid nanotechnology (NA-NTech) in immunotherapy, offering insights and references for designing next-generation immune-regulatory nanoplatforms.