Design of Spherical Nucleic Acids: From Fast Synthesis to Structural Engineering.

Since the introduction of the spherical nucleic acid (SNA) paradigm in 1996, extensive research has been dedicated to this burgeoning field, yielding groundbreaking advances in biomedicine. Featuring a unique three-dimensional spherical nanoarchitecture composed of highly oriented, densely packed oligonucleotide layers conjugated to a solid or hollow core, SNAs possess extraordinary biological properties, including transfection-reagent-independent cellular internalization and enhanced resistance to nuclease degradation. These synthetic and foundational evolutionary milestones offer profound advantages for the rational design of targeted biomedical therapeutics. In this comprehensive review, recent breakthroughs in the synthetic methodologies and structural designs of SNAs, with a particular emphasis on gold-based templates, are systematically summarized and discussed. Furthermore, the core bottlenecks and future perspectives emerging at the intersection of artificial intelligence and high-throughput screening are highlighted to guide next-generation intelligent nanomedicine development.