Functionalizing Framework Nucleic‐Acid‐Based Nanostructures for Biomedical Application

Abstract Strategies for functionalizing diverse tetrahedral framework nucleic acids (tFNAs) have been extensively explored since the first successful fabrication of tFNA by Turberfield. One‐pot annealing of at least four DNA single strands is the most common method to prepare tFNA, as it optimizes the cost, yield, and speed of assembly. Herein, the focus is on four key merits of tFNAs and their potential for biomedical applications. The natural ability of tFNA to scavenge reactive oxygen species, along with remarkable enhancement in cellular endocytosis and tissue permeability based on its appropriate size and geometry, promotes cell–material interactions to direct or probe cell behavior, especially to treat inflammatory and degenerative diseases. Moreover, the structural programmability of tFNA enables the development of static tFNA‐based nanomaterials via engineering of functional oligonucleotides or therapeutic molecules, and dynamic tFNAs via attachment of stimuli‐responsive DNA apparatuses, leading to potential applications in targeted therapies, tissue regeneration, antitumor strategies, and antibacterial treatment. Although there are impressive performance and significant progress, the challenges and prospects of functionalizing tFNA‐based nanostructures are still indicated in this review.