Nucleic acids have lately been explored as one of the significant strategies for cancer treatment. Despite their potential as a promising therapeutic tool in cancer therapy, these often face challenges of rapid degradation, insufficient cellular uptake, and poor targeting abilities. In this regard, nanotechnology has revolutionized nucleic acid-based cancer therapy. The current review explores role of various delivery carriers such as lipidic nanoparticles, polymeric nanoparticles, metallic nanoparticles, and quantum dots in facilitating the transport of nucleic acids, viz., plasmid DNA, siRNA, mRNA, and aptamers. Nanocarriers tend to protect nucleic acids from degradation, improve cellular internalization, and deliver nucleic acids to specific cellular regions, thereby improving their efficacy. In addition, this review provides a comprehensive overview of targeting strategies that address multiple biological barriers of systemic circulation to intracellular trafficking of nucleic acids, as well as advantages, limitations, and applications of each nanoparticles type. By analyzing the current state of scientific research and future advancements in clinical innovation, this review highlights the transformative potential and practical challenges to nanotechnology in nucleic acid-based cancer therapy.