Framework Nucleic Acids as a Nanocontainer for Delivering Heterogeneous Molecular Drugs

Framework nucleic acids (FNAs) are a class of nucleic acid-based nanostructures characterized by their unique precise structures, excellent biocompatibility and stability, robust loading capacity, and distinctive distribution and metabolic behaviors. They are widely applied in frontier fields such as nanodevices, biosensing, and drug delivery. In recent years, research on FNAs has gradually developed from the design and synthesis of nucleic acid nanostructures to practical applications, particularly in providing precise nanocontainers for heterogeneous molecular drugs such as small molecules, peptides, and proteins. Acting as a drug delivery system, FNA nanocontainers could be utilized to address multiple issues inherent in the application of heterogeneous molecular drugs, including hydrophobicity, affinity, and stability. However, they also face challenges such as low drug carrier capacity, potential immunogenicity, and insufficient long-term stability in vivo, necessitating the development of new strategies. This article focuses on composite drugs of small molecules, peptides, and proteins carried by FNAs, elucidates the design principles of FNA carriers, the interaction modes between FNAs and drug molecules, and the physicochemical properties and biological effects/efficacy of FNA-drug complexes, and summarizes the structure-activity relationship patterns. Furthermore, obstacles limiting clinical transformation are proposed to provide beneficial suggestions for the future development of FNA-based drugs.