Abstract:
DNA nanotechnology has emerged as a transformative platform in molecular medicine over the past four decades. The structural and functional versatility of nanostructures like DNA origami, hydrogels, and aptamer-based systems, as well as their programmable, biocompatible natures, have contributed toward significant advances in a biomedical context, such as cancer-targeted therapies, infectious disease detection, gene delivery, novel tissue engineering, and regenerative medicine. Despite promising preclinical experiment data, actual clinical translation remains limited in the face of key challenges–biostability, immunogenicity, scalable manufacturing, and regulatory hurdles. This review provides a comprehensive overview of the field's pathway from fundamental principles to viable, real-world, clinical solutions. These barriers are critically evaluated, with a focus on optimizing safety, delivery, and in-vivo performance, and discuss emerging strategies to overcome these limitations, including DNA–protein hybrids, protective coatings, responsive designs, harnessing AI capacity and automation-enabled production pipelines, by combining insights from basic science, engineering, and translational medicine.