Flexible Delivering Potential of Oligonucleotides Reconstructed DNA Tetrahedron

Abstract Tetrahedral framework nucleic acid (tFNA), a 3D nanostructure formed by four single‐stranded DNAs (ssDNAs), has shown great application potential for excellent editability, good biocompatibility, abundant bio‐functions, and superior drug loading capacity. However, mismatching and self‐agglomeration of tFNA composition structure have affected its yield and bioavailability. To address these issues, one chain of tFNA is re‐programmed into three short‐chain oligonucleotides, and then self‐assembled with the remaining three chains to form a DNA tetrahedron (oligonucleotides reconstructed DNA tetrahedron, ORT). ORT effectively improves the yield of DNA tetrahedron by reducing the mismatching. In addition, ORT could optimize the structure to minimize aggregation and enhance stability. The ORT with tetrahedral framework demonstrates good cellular internalization efficiency and tissue permeability. With further modifications, ORT would deliver various oligonucleotides as biological carrier. The ORT presents a new concept of breaking and reconstructing nanostructures, providing valuable insights for the development of novel nanomaterials and modification of nanostructures, which would bring more opportunities for the advances of DNA nanomedicine.