This review emphasized recent developments in gene therapy with rationally created nucleic acid nanocarriers. Antisense, RNAi, gene editing, and gene expression therapeutic techniques were highlighted. Structurally programmable, spatially adjustable and biocompatible nucleic acid nanostructures have been evolved as superior loading vehicles for homologous nucleic acid treatments such as antisense, siRNA, shRNA, sgRNA, linear genes, and mRNA. Multiple functional components, including active targeting groups and stimulant-responsive elements, may also be readily inserted into nucleic acid nanocarriers for targeted distribution and controlled release of nucleic acid drugs, helping to minimize systemic toxicity and improve pharmacodynamics. Until recently, the practical application of nucleic acid nanocarriers for the delivery of in vivo nucleic acid therapy remained uncertain. First, the systemic pharmacokinetics of nucleic acid nanostructures, including circulation, distribution, metabolism, and excretion, should be carefully investigated. Second, additional study is needed on the actual cellular internalization processes and intracellular fate of nucleic acid nanostructures of diverse shapes and sizes. Lastly, unmethylated CpG motifs and dsRNA can activate innate immune activation. Fortunately, improving nucleic acid sequences can dramatically decrease immune reactions to nucleic acid nanostructures. Uchida and coworkers observed, for example, that lowering the hybridization length to 17 nt can suppress immune reactions caused by dsRNA. Despite the foregoing constraints, developed nucleic acid nanostructures with different benefits are expected to act as intelligent delivery carriers for gene-related medicines. The nucleic acid nanocarriers have not yet been evaluated in the clinic due to long-term storage and fabrication costs. Many lyophilization-based techniques, including cryopreservation, have been studied for the long-term storage of nucleic acid molecules. Moreover, as biotechnology improves in nucleic acid mass manufacturing, the cost of nucleic acid nanocarriers is projected to drop considerably. According to our projections, preclinical and clinical research based on nucleic acid nanostructures is predicted to begin soon.