Dimensional control of DNA nanostructures enhances cellular uptake and guides tissue-regenerative responses

Precise regulation of cellular functions is fundamental for advancing tissue regeneration and drug delivery systems. Structural DNA nanotechnology enables the design of well-defined nanostructures, emerging as a promising platform in these biomedical applications. However, a clear understanding of how the dimensional properties of DNA nanostructures affect cellular uptake and biological responses remains limited. In this study, we constructed three distinct DNA nanostructures: a one-dimensional six-helix bundle (6HB), a two-dimensional three-point star, and a three-dimensional tetrahedron. We systematically evaluated their endocytic efficiency in five representative cell types: endothelial cells, dermal fibroblasts, myoblasts, chondrocytes, and osteoblasts. Among them, the 6HB exhibited the highest cellular uptake, with minimal variability across cell types in both 2D petri dish cultures and 3D multicellular spheroid invasion models. Moreover, DNA nanostructures were found to enhance cell proliferation in fibroblasts and chondrocytes, support chondrocyte phenotype maintenance, and, in the case of the 6HB, promote myoblast differentiation. These findings provide new insights into structure–function relationships in DNA nanomaterials and offer guidance for optimizing DNA-based platforms for drug delivery and regenerative medicine.