Advanced Nucleic Acid Architectures: Classification, Assembly Mechanisms, and Biomedical Applications

Nucleic acids are increasingly exploited as programmable molecular materials for nanomedicine, biosensing, and biomaterials engineering, but their biomedical deployment remains constrained by nuclease degradation, inefficient membrane transport, endosomal sequestration, rapid clearance, and potential immune activation. This Review presents a role-based framework for advanced nucleic acid architectures according to the contribution of nucleic acids to final structure, spanning nucleic acid-dictated architectures, supramolecular nucleic acid co-assemblies, and nucleic acid-loaded composite biomaterials, including sequence-defined genetic cargos and non-sequence-defined PDRN-based regenerative systems. We compare sequence-directed hybridization, electrostatic condensation, metal–ligand coordination, polyamine- and polyphenol-mediated interactions, and carrier- or matrix-confined assembly, and relate these mechanisms to structural stability, nuclease resistance, cellular transport, intracellular release, stimulus responsiveness, and biological activity. Applications in drug and nucleic acid delivery, molecular diagnostics, regenerative and skin-repair biomaterials, vaccination, and immunomodulation are critically evaluated. Across platforms, architecture emerges as a formulation variable that must balance molecular protection with functional release, productive delivery, biosafety, and manufacturability. Translational development requires quantitative structure–performance relationships, standardized characterization, stability assessment, scalable processing, and context-specific pharmacokinetic and regulatory evaluation. This integrated perspective provides design principles for the rational pharmaceutical development of advanced nucleic acid systems.