The host innate immune system orchestrates frontline protection towards pathogens by using germline-encoded sample recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs), that are conserved molecular buildings distinctive to microbes[1], [2]. Whereas nucleic acids, consisting of DNA and RNA, function indispensable genetic supplies important for pathogen propagation, their recognition by PRRs constitutes a elementary mechanism in activating innate immunity[3]. On this course of, quite a lot of DNA and RNA recognition proteins are concerned, primarily together with toll-like receptors (TLRs)[4], retinoic acid-inducible gene I (RIG-I) -like receptors (RLRs)[5], nucleotide-binding oligomerization area (NOD)-like receptors (NLRs)[6], and cyclic guanosine monophosphate (GMP)- adenosine monophosphate (AMP) synthase (cGAS)[7]. The interaction between these nucleic acid sensors and their downstream signaling pathways highlights the complexity of the innate immune system and demonstrates the exact self/non-self discrimination.
Over the previous few many years, the sphere of NA-NTech has developed quickly, from the foundational growth of DNA duplexes to the creation of complicated, multidimensional architectures exemplified by DNA/RNA origami[8], [9], [10], [11]. These nanostructures, assembled by exactly engineered nucleic acids, have demonstrated outstanding functions in biomedical fields, corresponding to drug supply and therapeutic intervention[12], [13], [14]. Notably, as NA-NMat leverage the inherent properties of nucleic acids, they maintain intrinsic immunostimulatory potential[15], [16], [17], [18], [19]. This characteristic emphasizes the necessity for a complete understanding of the immunogenic profiles of those nanostructures for his or her protected deployment in vivo. As well as, the excessive programmability of NA-NMat additionally offers a novel platform to review and modulate innate immune responses.
Earlier research in immunology have systematically elucidated the molecular mechanisms by which cells acknowledge “non-self” nucleic acids[3], [20], whereas the sphere of NA-NMat has established the therapeutic basis of nucleic acid buildings in immunotherapy[17], [18], [19], [21]. A greater understanding of how nucleic acids activate innate immunity via their hierarchical structural options (e.g., major, secondary, tertiary, and higher-order buildings) may help us recognize the vital roles of nucleic acids in immunomodulation and uncover their therapeutic potential. On this overview, we undertake, for the primary time to our information, a structure-centric classification framework to systematically correlate distinct structural traits (corresponding to sequence motifs, duplex conformations, and spatial folding patterns) with particular innate immune activation pathways. Concurrently, we emphasize latest developments in useful module-integrated NA-NMat and their therapeutic functions, with the goal to ascertain a structural basis for the deliberate design of immunomodulatory nucleic acid supplies (Fig. 1).
