The modernization of Traditional Chinese Medicine (TCM) faces considerable challenges, primarily due to the poor water solubility, low chemical stability, and limited oral bioavailability of its active components. These limitations hinder the translation of Natural Compounds from Chinese Herbal Medicine (NCCHMs) from basic research to clinical applications. Recently, the advent of DNA nanotechnology has provided innovative solutions to address these challenges. Among these, tetrahedral framework nucleic acids (tFNAs), a novel class of programmable nanomaterials, show significant promise as ideal drug delivery carriers. Their precisely controllable three-dimensional structure, excellent biocompatibility, low immunogenicity, efficient cellular uptake, and remarkable ability to penetrate biological barriers contribute to their potential. This review systematically examines the latest advancements in using tFNAs as efficient delivery platforms to enhance the therapeutic efficacy of NCCHMs against various diseases. It begins with an overview of tFNA synthesis, key physicochemical properties, and inherent biological effects, before exploring the passive targeting capability of tFNAs. This capability allows for efficient drug delivery to target organs, such as the liver, kidneys, brain, and joints, through various administration routes. The core section focuses on strategies for conjugating tFNAs with various natural compounds and active components from TCM, including groove binding, intercalation, and covalent linkage. Drawing on studies from diverse disease models-such as obesity, radiation-induced cystitis, osteoarthritis, acute kidney injury, and diabetic retinopathy-the review demonstrates that tFNA-NCCHMs significantly enhance drug stability, increase target-site concentration, reduce toxic side effects, and provide synergistic therapeutic effects.Finally, this review provides future perspectives, highlighting the potential of tFNA-NCCHMs in advancing TCM from an "empirical medicine" to an "evidence-based" precision medicine approach. With precise functionalization modifications (e.g., targeting peptides, stimulus-responsive elements), stability optimization, and interdisciplinary integration with fields such as artificial intelligence and immunotherapy, the tFNA-NCCHMs delivery system holds great promise for the modernization and global integration of TCM.
Liang et al. (Wed,) studied this question.