Locked Nucleic Acid Modification for Base‐Stacking Engineering of Self‐Assembled DNA Crystals

作者：Jielin Chen, Mingqiang Li, Ziyu Li, Yuqing Tang, Hanwei Zhang, Jianing Cheng, Zheze Dai, Xiaolei Zuo, Qian Li, Fei Wang, Sisi Jia, Hui Lv, Chunhai Fan, Xiaoguo Liu · 发表于：Angewandte Chemie · 年份：2025 · DOI：10.1002/ange.202511377 · 研究领域：Advanced biosensing and bioanalysis techniques、Bacteriophages and microbial interactions、DNA and Nucleic Acid Chemistry

Abstract DNA hybridization and assembly processes are governed by the concerted effects of Watson–Crick pairing and base‐stacking interactions. While sequence engineering and chemical modifications have been extensively exploited to regulate DNA hybridization processes and complex structural assembly of DNA, here we demonstrate the use of locked nucleic acid (LNA) modifications to finely tune base‐stacking interactions, which are yet to be explored in DNA assembly processes, to program the growth of self‐assembled DNA crystals. We find that sticky‐end LNA modifications decrease base‐pair spacing and enhance base‐stacking energy, which synergistically improves interstrand affinity and accelerates hybridization rate constants, as revealed by strand displacement kinetics, molecular dynamics simulations, and small‐angle X‐ray scattering analysis. This LNA‐based base‐stacking engineering strategy can finely tune base‐stacking energy landscapes to drive anisotropic growth and morphological control in self‐assembled DNA crystal. We further establish a quantitative framework for probing structure–energy relationships in base‐stacking interactions, which not only paves the way for better control of structural DNA nanotechnology but also provides mechanistic insights for developing dynamic DNA nanosystems.