Topology-guided design of polyvalent functional nucleic acids

Functional nucleic acids (FNAs) have traditionally been optimized through sequence selection and chemical modification of nucleobases, glycosyls, and phosphate backbones. Beyond these strategies, the topological architecture of FNAs is emerging as an important but underdefined design dimension. In recent years, polyvalent FNAs (pFNAs) assembled from aptamers, DNAzymes, and DNA origami have been engineered into linear, planar, spherical, and framework architectures, exhibiting functional advantages over monovalent FNAs in various biological applications. However, how topological architecture shapes pFNAs’ behavior remains unclear. From a biomimetic evolutionary perspective, this review systematically summarizes the evolution from monovalent units to polyvalent nucleic acids, higher-order polyvalent architectures, and hybrid polyvalent complexes, highlighting topology-guided pFNA engineering as a route from empirical assembly toward predictable and programmable precision theranostics.